Mechanisms for pro matrix metalloproteinase activation

Murphy, Gillian; Stanton, Heather; Cowell, Susan; Butler, Georgina S.; Knäuper, Vera; Atkinson, Susan J.; Gavrilović, Jelena

doi:10.1111/j.1699-0463.1999.tb01524.x

Cited by 440 publications

(339 citation statements)

References 44 publications

Supporting

Mentioning

328

Contrasting

Unclassified

Order By: Relevance

“…MT1-MMP requires proteolytic activation and the removal of the N-terminal prodomain sequence in order to be converted into the catalytically active species (Murphy et al, 1999). Activation by PCs occurs in the secretory pathway of the de novo synthesized MT1-MMP and this process is tightly linked to the presentation and, consequently, to the activity of cellular MT1-MMP (Seidah and Prat, 2002;Osenkowski et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

et al. 2006

View full text Add to dashboard Cite

Invasion-promoting membrane type-1 matrix metalloproteinase (MT1-MMP) functions in cancer cells as an oncogene and as a mediator of proteolytic events on the cell surface. To exert its functional activity, MT1-MMP requires proteolytic removal of the prodomain sequence. There are two potential furin cleavage motifs, R 89 -R-P-R-C 93 and R 108 -R-K-R-Y 112 , in the prodomain sequence of MT1-MMP. Our data suggest an important role of furin and related proprotein convertases (PCs) in mediating both the activation of MT1-MMP and the levels of functionally active MT1-MMP at the surface of cancer cells. We have determined that the peptide sequence that spans the first cleavage site is susceptible to furin and PC5/6, whereas the second sequence is susceptible to furin and also to PC5/6, PC7 and PACE4. In the structure of the MT1-MMP proenzyme, the R 89 -R-P-R-C 93 site, however, is inaccessible to PCs. Our studies also demonstrated a direct functional link between the activation and the uptake rate of the proenzyme and the enzyme of MT1-MMP. Thus, the uptake rate of the latent MT1-MMP proenzyme noticeably exceeded that of the active enzyme. We conclude that furin and related PCs are the essential components of the specialized cellular machinery that controls the levels of the functionally active, mature, MT1-MMP enzyme on the cell surface to continually support the potency of pericellular proteolysis.

show abstract

Section: Discussionmentioning

confidence: 99%

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Cathepsin B-positive cells often coexpressed HAM56 too, which is a known marker for mononuclear macrophages in GCTTS (2,40). Cathepsin B may be involved in cartilage and bone destruction by degrading proteoglycans, different collagen types (II, IX, and XI), and the bone matrix protein osteocalcin as well as by activating the collagenolytic metalloproteinases interstitial collagenase (MMP-1) and stromelysin (17)(18)(19). The expression of both MMP-1 and MMP-3 has been examined in pigmented villonodular synovitis, which is considered to be a closely related entity of GCTTS.…”

Section: Discussionmentioning

confidence: 99%

Expression of Cysteine Proteinases Cathepsins B and K and of Cysteine Proteinase Inhibitor Cystatin C in Giant Cell Tumor of Tendon Sheath

Hansen

Gäumann

et al. 2001

Modern Pathology

View full text Add to dashboard Cite

The expression of cysteine proteinases cathepsins B and K and of the endogenous inhibitor of cysteine proteinases, cystatin C, was investigated in tissue specimens of patients with giant cell tumor of tendon sheath (GCTTS). Expression of both enzymes was examined by immunohistochemistry in tissue specimens of 14 patients with GCTTS. Applying double-labeling techniques, the coexpression of cathepsin B and its major endogenous inhibitor cystatin C was additionally studied. Cells expressing the respective proteins were further characterized with the macrophage markers HAM56 and anti-CD68 (clone PG-M1). Cathepsin B could be detected in numerous HAM56-positive mononuclear cells (MC), but only in very few giant cells (GC). In contrast, cathepsin K was predominantly identified in GC that were also strongly immunoreactive for cystatin C and CD68. Coexpression of cathepsin B and cystatin C occurred only in a few MC. The strong expression of both cathepsin B and K suggests that in GCTTS, bone erosion might be mediated not only by pressure of the proliferative tissue, but also by matrix-degrading cysteine proteinases. Because previous studies showed that osteoclasts express high levels of CD68, cathepsin K, and cystatin C but not of cathepsin B, our study contributes to the view that GC of GCTTS and osteoclasts are closely associated.

show abstract

“…This mechanism is not fully understood, but involves membrane-type MMPs (MT-MMPs) such as MT1-MMP (MMP-14), the most potent activator of MMP-2 by cleaving the N-terminal domain of ProMMP-2 (Sato et al, 1994;Cao et al, 1995). The endogenous inhibitor of MMP-2, tissue inhibitor of metalloproteinases -2 (TIMP-2) has been shown to inhibit both the activation of MMP-2 and activity of MMP-2 by blocking further cleavage of the proform active site cleft and blocking the catalytic domain of both active MMP-2 and MMP-14 Corcoran et al, 1996;Murphy et al, 1999). Moreover, steady state levels of TIMP-2 mRNA have been shown to decrease in the fibrous sclera of chick eyes which are actively elongating, and increase in the sclera of chick eyes which are slowing their rate of axial elongation, suggesting that TIMP-2 plays a role in the regulation of scleral extracellular matrix remodeling in chick sclera associated with changes in ocular elongation rates (Rada et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Shelton

Rada

2007

Experimental Eye Research

View full text Add to dashboard Cite

In order to understand the effect of mechanical strain on scleral extracellular matrix remodeling, human scleral fibroblasts were subjected to equibiaxial stretch in vitro and the expression of proteoglycans, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were evaluated.Isolated human scleral fibroblasts were seeded onto flexible bottom culture plates, and subjected to a cyclic stretch regimen of 15% equibiaxial stretch for 45 seconds followed by 15 seconds of rest for 6 -48 hours in the presence of 35 SO 4 . Newly synthesized proteoglycans were measured in the medium by CPC precipitation of radiolabelled glycosaminoglycans. MMP-2 activity and expression levels were measured in the medium by, Western blot, gel zymography and real-time PCR. Steady state levels of TIMP-2 mRNA and membrane-type MMP, MT1-MMP (MMP-14) mRNA were measured in the cell layer using real-time PCR.The predominant gelatinolytic enzyme secreted by scleral fibroblasts was the pro-enzyme form of MMP-2 (ProMMP-2). Mechanical stretch resulted in a significant increase of ProMMP-2 after 12 and 48 hours (+76.28%, p < 0.05; +19.56%, p < 0.01, respectively). Mechanical stretch significantly increased the production of the active form of MMP-2 (ActiveMMP-2) after 48 hours (+59.72%, p < 0.05) and decreased levels of TIMP-2 mRNA (−22%, p < 0.05). The rate of scleral proteoglycan synthesis and the steady state levels of MMP-2 and MMP-14 mRNA were not significantly affected by mechanical stretch.These results suggest that mechanical strain stimulates the activation of MMP-2 by scleral fibroblasts, possibly through increased levels of ProMMP-2 and reduced levels of TIMP-2. Increased levels of ActiveMMP-2 in the sclera would be expected to contribute to scleral extracellular matrix degradation, scleral thinning and possible ocular ectasia.

show abstract

Mechanisms for pro matrix metalloproteinase activation

Cited by 440 publications

References 44 publications

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

Expression of Cysteine Proteinases Cathepsins B and K and of Cysteine Proteinase Inhibitor Cystatin C in Giant Cell Tumor of Tendon Sheath

Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts

Contact Info

Product

Resources

About