Tissue inhibitor of metalloproteinase (TIMP)-2 acts synergistically with synthetic matrix metalloproteinase (MMP) inhibitors but not with TIMP-4 to enhance the (Membrane type 1)-MMP-dependent activation of pro-MMP-2.
The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been shown to be a key enzyme in tumor angiogenesis and metastasis. MT1-MMP hydrolyzes a variety of extracellular matrix components and is a physiological activator of pro-MMP-2, another MMP involved in malignancy. Pro-MMP-2 activation by MT1-MMP involves the formation of an MT1-MMP.tissue inhibitors of metalloproteinases 2 (TIMP-2). pro-MMP-2 complex on the cell surface that promotes the hydrolysis of pro-MMP-2 by a neighboring TIMP-2-free MT1-MMP. The MT1-MMP. TIMP-2 complex also serves to reduce the intermolecular autocatalytic turnover of MT1-MMP, resulting in accumulation of active MT1-MMP (57 kDa) on the cell surface. Evidence shown here in Timp2-null cells demonstrates that pro-MMP-2 activation by MT1-MMP requires TIMP-2. In contrast, a C-terminally deleted TIMP-2 (Delta-TIMP-2), unable to form ternary complex, had no effect. However, Delta-TIMP-2 and certain synthetic MMP inhibitors, which inhibit MT1-MMP autocatalysis, can act synergistically with TIMP-2 in the promotion of pro-MMP-2 activation by MT1-MMP. In contrast, TIMP-4, an efficient MT1-MMP inhibitor, had no synergistic effect. These studies suggest that under certain conditions the pericellular activity of MT1-MMP in the presence of TIMP-2 can be modulated by synthetic and natural (TIMP-4) MMP inhibitors.
Toth
M
M
Departments of Pathology, Urology and Chemistry, Wayne State University, Detroit, Michigan 48201, USA.
Bernardo
M M
MM
Gervasi
D C
DC
Soloway
P D
PD
Wang
Z
Z
Bigg
H F
HF
Overall
C M
CM
DeClerck
Y A
YA
Tschesche
H
H
Cher
M L
ML
Brown
S
S
Mobashery
S
S
Fridman
R
R
D000818:Animals; D002460:Cell Line; D004357:Drug Synergism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D004792:Enzyme Precursors; D020778:Matrix Metalloproteinase 2; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D011480:Protease Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4