scholarly journals Plasma Membrane-bound Tissue Inhibitor of Metalloproteinases (TIMP)-2 Specifically Inhibits Matrix Metalloproteinase 2 (Gelatinase A) Activated on the Cell Surface

1998 ◽  
Vol 273 (38) ◽  
pp. 24360-24367 ◽  
Author(s):  
Yoshifumi Itoh ◽  
Akira Ito ◽  
Kazushi Iwata ◽  
Kazuhiko Tanzawa ◽  
Yo Mori ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Gelatinase A ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor ◽  
Membrane Bound

scholarly journals Steps involved in activation of the complex of pro-matrix metalloproteinase 2 (progelatinase A) and tissue inhibitor of metalloproteinases (TIMP)-2 by 4-aminophenylmercuric acetate

1995 ◽  
Vol 308 (2) ◽  
pp. 645-651 ◽  
Author(s):  
Y Itoh ◽  
S Binner ◽  
H Nagase
Keyword(s):  
Matrix Metalloproteinase ◽  
Noncovalent Complex ◽  
The Other ◽  
Gelatinolytic Activity ◽  
Matrix Metalloproteinase 2 ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor ◽  
Sh Group ◽  
Inhibitory Domain ◽  
Interstitial Collagenase

Tissue inhibitor of metalloproteinases (TIMP)-2 forms a noncovalent complex with the precursor of matrix metalloproteinase 2 (proMMP-2, progelatinase A) through interaction of the C-terminal domain of each molecule. We have isolated the proMMP-2-TIMP-2 complex from the medium of human uterine cervical fibroblasts and investigated the processes involved in its activation by 4-aminophenylmercuric acetate (APMA). The treatment of the complex with APMA-activated proMMP-2 by disrupting the Cys73-Zn2+ interaction of the zymogen. This is triggered by perturbation of the proMMP-2 molecule, but not by the reaction of the SH group of Cys73 with APMA. The ‘activated’ proMMP-2 (proMMP-2*) formed a new complex with TIMP-2 by binding to the N-terminal inhibitory domain of the inhibitor without processing the propeptide. Thus the APMA-treated proMMP-2*-TIMP-2 complex exhibited no gelatinolytic activity. In the presence of a small amount of free MMP-2, however, proMMP-2* in the complex was converted into the 65 kDa MMP-2 by proteolytic attack of MMP-2, but the complex did not exhibit gelatinolytic activity. The gelatinolytic activity detected after APMA treatment was solely derived from the activation of free proMMP-2. The removal of the propeptide of the proMMP-2* bound to TIMP-2 was also observed by MMP-3 (stromelysin 1), but not by MMP-1 (interstitial collagenase). MMP-3 cleaved the Asn80-Tyr81 bond of proMMP-2*. On the other hand, when MMP-3 was incubated with the proMMP-2-TIMP-2 complex, it bound to TIMP-2 and rendered proMMP-2 readily activatable by APMA. These results indicate that the blockage of TIMP-2 of the complex with an active MMP is essential for the activation of proMMP-2 when it is complexed with TIMP-2.

scholarly journals Plasma profiling determinants of matrix homeostasis in paediatric dilated cardiomyopathy

2010 ◽  
Vol 21 (1) ◽  
pp. 52-61 ◽  
Author(s):  
Tain-Yen Hsia ◽  
Jeremy M. Ringewald ◽  
Robert E. Stroud ◽  
Nadia Roessler ◽  
Nidhi Kumar ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Matrix Metalloproteinase ◽  
Dilated Cardiomyopathy ◽  
Plasma Levels ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Matrix Metalloproteinase 2 ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor ◽  
Tissue Inhibitors ◽  
Tissue Inhibitors Of Metalloproteinase

AbstractObjectiveDilated cardiomyopathy is an important cause of cardiac failure in both children and adults, but is more progressive in children. In adult dilated cardiomyopathy, left ventricular remodelling is associated with changes in the plasma levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases. Plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase changes in paediatric dilated cardiomyopathy have not been examined. This study developed a low blood volume, high-sensitivity assay to test the hypothesis that unique and differential plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase profile exist in patients with paediatric dilated cardiomyopathy.Methods/resultsA systemic blood sample (1 millilitre) was obtained from seven children aged 8 plus or minus 7 years with dilated cardiomyopathy and 26 age-matched normal volunteers. Using a high-throughput multiplex suspension immunoassay, plasma levels were quantified for collagenases (matrix metalloproteinase-8), gelatinases (matrix metalloproteinase-2 and -9), lysins (matrix metalloproteinase-3 and -7), and tissue inhibitor of metalloproteinases-1, -2, and -4. The matrix metalloproteinase to tissue inhibitors of metalloproteinases ratios were also calculated. The plasma matrix metalloproteinase-2, -7, -8, and -9 levels were increased by greater than twofold in patients with dilated cardiomyopathy than normal patients (with p less than 0.05). Patients with dilated cardiomyopathy also had significantly higher tissue inhibitors of metalloproteinases-1 and -4 (298% and 230%; with p less than 0.05).ConclusionsThese unique findings show that a specific plasma matrix metalloproteinase/tissue inhibitor of metalloproteinase profile occurs in paediatric dilated cardiomyopathy when compared to the cases of normal children. These distinct differences in the determinants of myocardial matrix structure and function may contribute to the natural history of dilated cardiomyopathy in children and may provide a novel biomarker platform in paediatric dilated cardiomyopathy.

scholarly journals MT1-MMP hemopexin domain exchange with MT4-MMP blocks enzyme maturation and trafficking to the plasma membrane in MCF7 cells

2006 ◽  
Vol 398 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Susan J. Atkinson ◽  
Christian Roghi ◽  
Gillian Murphy
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Mcf7 Cells ◽  
Matrix Metalloproteinase 1 ◽  
Cell Surface Biotinylation ◽  
Membrane Type ◽  
Hemopexin Domain

The hemopexin-like domain of membrane-type matrix metalloproteinase-1 (MT1-MMP) enables MT1-MMP to form oligomers that facilitate the activation of pro-matrix metalloproteinase-2 (pro-MMP-2) at the cell surface. To investigate the role of the MT1-MMP hemopexin domain in the trafficking of MT1-MMP to the cell surface we have examined the activity of two MT1–MT4-MMP chimaeras in which the hemopexin domain of MT1-MMP has been replaced with that of human or mouse MT4-MMP. We show that MT1-MMP bearing the hemopexin domain of MT4-MMP was incapable of activating pro-MMP-2 or degrading gelatin in cell based assays. Furthermore, cell surface biotinylation and indirect immunofluorescence show that transiently expressed MT1–MT4-MMP chimaeras failed to reach the plasma membrane and were retained in the endoplasmic reticulum. Functional activity could be restored by replacing the MT4-MMP hemopexin domain with the wild-type MT1-MMP hemopexin domain. Subsequent analysis with an antibody specifically recognising the propeptide of MT1-MMP revealed that the propeptides of the MT1–MT4-MMP chimaeras failed to undergo proper processing. It has previously been suggested that the hemopexin domain of MT4-MMP could exert a regulatory mechanism that prevents MT4-MMP from activating pro-MMP-2. In this report, we demonstrate unambiguously that MT1–MT4-MMP chimaeras do not undergo normal trafficking and are not correctly processed to their fully active forms and, as a consequence, they are unable to activate pro-MMP-2 at the cell surface.

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