Binding of latent matrix metalloproteinase 9 to fibrin: activation via a plasmin-dependent pathway.
The binding of two matrix metalloproteinases (MMP) to fibrin was evaluated. MMP-2 (72-kDa) and MMP-9 (92-, 130-, and 225-kDa) were selected since both contain a fibronectin-like region and fibronectin binds fibrin. Gelatin zymography indicated selective and dose dependent binding of MMP-9 to fibrin. No MMP-2 binding to fibrin occurred. Densitometry revealed that the 130- and 225-kDa forms demonstrated similar sigmoidal binding profiles whereas 92-kDa uptake was hyperbolic. Fibronectin and TIMP-1 competition studies indicated that the fibronectin and C-terminal MMP-9 domains, respectively, were not involved with fibrin binding. The MMP-9 collagen-like region may be of regulatory significance since type I and II fibrillar and type IV basement membrane collagens demonstrated fibrin binding. During fibrinolysis, latent fibrin-bound MMP-9 was processed to lower molecular weight forms consistent with proteolytic activation. This process was inhibited by epsilon-aminocaproic acid, indicating a plasmin-dependent pathway. The significance of these findings to procoagulant activity and MMP-mediated extracellular matrix destruction during inflammation and tumor invasion and metastasis is discussed.
Makowski
G S
GS
Department of Laboratory Medicine, University of Connecticut Health Center, Farmington, USA.
Ramsby
M L
ML
D017364:Collagenases / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005337:Fibrin / Q000378:metabolism*; D005341:Fibrinolysin / Q000502:physiology*; D018093:Gelatinases / Q000097:blood / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000097:blood / Q000378:metabolism; D008970:Molecular Weight; D009504:Neutrophils / Q000737:chemistry; D013997:Time Factors; D014020:Tissue Extracts / Q000378:metabolism
D014020:Tissue Extracts; D005337:Fibrin; D005341:Fibrinolysin; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9