Expression of Three Membrane-type Matrix Metalloproteinases (MT-MMPs) in Rat Vascular Smooth Muscle Cells and Characterization of MT3-MMPs with and without Transmembrane Domain

Shofuda, Ken-ichi; Yasumitsu, Hidetaro; Nishihashi, Ai; Miki, Keizaburo; Miyazaki, Kaoru

doi:10.1074/jbc.272.15.9749

Cited by 111 publications

(108 citation statements)

References 45 publications

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“…In addition to being relevant for the shedding of betaglycan, this effect of MT2-MMP may have wider consequences because it implies that MT2-MMP is capable of down-regulating MT1-MMP. To our knowledge, there are four reports that show concomitant expression of these two metalloproteases, in glioblastoma tissues (68), in pancreatic tumor cell lines (60), in primary cultures of smooth muscle cells from aorta (69), and in placenta tissues (70). Nonetheless, in view of the paramount importance that MT1-and MT2-MMPs have in the invasiveness, morphogenesis, and metastatic potential of epithelial cells (71,72), this observation deserves further investigation.…”

Section: Overexpression Of Mt1-or Mt3-mmps Augments the Shedding Of Smentioning

confidence: 95%

The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

Velasco-Loyden

Arribas

López‐Casillas

2004

Journal of Biological Chemistry

125

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Betaglycan is a membrane-anchored proteoglycan that binds transforming growth factor-␤ (TGF-␤) via its core protein. A soluble form of betaglycan can be released by proteolytic cleavage (also known as shedding) of the membrane-bound form, yielding soluble betaglycan. The mechanism leading to the generation of soluble betaglycan is poorly understood. Because the membrane and soluble forms of betaglycan have opposite effects regulating the availability of TGF-␤, it is important to characterize the shedding of betaglycan further. Here we present evidence showing that in certain cell types, pervanadate, a general tyrosine phosphatase inhibitor, induces the release of the previously described fragment that encompasses almost the entire extracellular domain of betaglycan (sBG-120). In addition, treatment with pervanadate unveils the existence of a novel 90-kDa fragment (sBG-90). Noticeably, the cleavage that generates sBG-90 is mediated by a tissue inhibitor of metalloprotease-2-sensitive protease. Overexpression of all membrane type matrix metalloproteases (MT-MMPs) described to date indicates that MT1-MMP and MT3-MMP are endowed with ability to generate sBG-90. Furthermore, the patterns of expression of different MTMMPs in the cell lines used in this study suggest that MT1-MMP is the protease involved in the shedding of sBG-90. Overexpression of MT1-MMP in COS-1 cells, which do not express detectable levels of this metalloprotease, confirms the feasibility of this hypothesis. Unexpectedly, during the course of these experiments, we observed that MT2-MMP decreases the levels of MT1-MMP and betaglycan. Finally, binding competition experiments indicate that, similar to the wild type membrane betaglycan, sBG-90 binds the TGF-␤2 isoform with greater affinity than TGF-␤1, suggesting that once released, it could affect the cellular availability of TGF-␤.

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Section: Overexpression Of Mt1-or Mt3-mmps Augments the Shedding Of Smentioning

confidence: 95%

The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

Velasco-Loyden

Arribas

López‐Casillas

2004

Journal of Biological Chemistry

125

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“…Additional dialyses were performed for 24 hours against Tris assay buffer (50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 5 mM CaCl 2 , 1 µM ZnCl 2 ). The refolded cdMT3 (with residues Metl-Tyrl20 MT3 -...-Pro307 MT3 ) 38 was concentrated by ultra-filtration (3-kDa cutoff, YM3 membrane, Amicon), and the precipitate was removed by centrifugation after incubation overnight at 4°C. The supernatant was subjected to a HitrapQ anion-exchange column (5 ml, Pharmacia) equilibrated with 50 mM Tris-HCl (pH 7.5) and 5 mM CaCl 2 , and eluted with a NaCl gradient (0-500 mM) in 50 mM Tris-HCl (pH 7.5), and the peak fractions containing the homogenous cdMT3 were pooled.…”

Section: Cloning Expression Refolding and Purification Of Cdmt3-mmpmentioning

confidence: 99%

“…39 MT3-MMP bears particularly strong sequence homology with MT5-MMPs. 21,22,38 Like MT1-MMP, it is inhibited by TIMP-2 but not by TIMP-1. 40 More efficiently than MT1-MMP does MT3-MMP digest type III collagen into typical one-and-three-quarter fragments, while it cleaves type I collagen only at the Gly4-Ile5 bond of the triple helical portion of the α2(I) chain.…”

Section: Introductionmentioning

confidence: 99%

“…Miyazaki and colleagues later published the slightly different cDNA sequence from human brain, which now seems to be generally accepted as the human MT3-MMP. 38 Besides, a soluble human MT3-MMP species formed by alternative splicing has been described. 39 MT3-MMP bears particularly strong sequence homology with MT5-MMPs.…”

Section: Introductionmentioning

confidence: 99%

“…The residue numbers refer to the sequence of the translated preproMT3-MMP molecule. 22,38 While MT-MMPs 1 and 2 are expressed in a variety of adult human tissues, expression of the MT-MMPs 3 and 5 seems to be restricted normally to the brain and the heart. 21,32,33 MT3-MMP, like MT1-MMP, is highly expressed in cancerous tissues compared with normal tissues.…”

Section: Introductionmentioning

confidence: 99%

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Crystal Structure of the Catalytic Domain of MMP-16/MT3-MMP: Characterization of MT-MMP Specific Features

Lang

Braun

Sounni

et al. 2004

Journal of Molecular Biology

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Membrane-type matrix metalloproteinases (MT-MMPs) have attracted strong attention, because four of them can activate a key player in the tumor scenario, proMMP-2/progelatinase A. In addition to this indirect effect on the cellular environment, these MT-MMPs degrade extracellular matrix proteins, and their overproduction is associated with tumor growth. We have solved the structure of the catalytic domain (cd) of MT3-MMP/MMP-16 in complex with the hydroxamic acid inhibitor batimastat. CdMT3-MMP exhibits a classical MMP-fold with similarity to MT1-MMP Nevertheless, it also shows unique properties such as a modified MT-specific loop and a closed S1' specificity pocket, which might help to design specific inhibitors. Some MT-MMP-specific features, derived from the crystal structures of MT-1-MMP determined previously and MT3-MMP, and revealed in recent mutagenesis experiments, explain the impaired interaction of the MT-MMPs with TIMP-1. Docking experiments with proMMP-2 show some exposed loops including the MT-loop of cdMT3-MMP involved in the interaction with the proMMP-2 pro-domain in the activation encounter complex. This model might help to understand the experimentally proven importance of the MT-loop for the activation of proMMP-2.

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Presence of high levels of MT1-MMP protein in fibroblastic cells of human invasive carcinomas

et al. 1999

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Matrix metalloproteinase 2 (MMP2) activity is associated with the aggressiveness of human cancers. Therefore, the mechanisms regulating its activation are of great interest for a better understanding of malignant invasive processes. MT1‐MMP, a membrane‐bound MMP, is involved in the conversion of the latent form of MMP2 to the active one. In the present study, we have raised 3 monoclonal antibodies (Mabs) directed against 3 different epitopes of human MT1‐MMP, which we used to investigate the expression and cellular localization of MT1‐MMP protein in human carcinomas. MT1‐MMP protein was present in all invasive carcinomas tested, and it was almost exclusively located to the stromal cells and not to cancer cells as previously reported, suggesting that MMP2 activation might be a peri‐fibroblastic event. Int. J. Cancer 82:208–212, 1999. © 1999 Wiley‐Liss, Inc.

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Expression of Three Membrane-type Matrix Metalloproteinases (MT-MMPs) in Rat Vascular Smooth Muscle Cells and Characterization of MT3-MMPs with and without Transmembrane Domain

Cited by 111 publications

References 45 publications

The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1

Crystal Structure of the Catalytic Domain of MMP-16/MT3-MMP: Characterization of MT-MMP Specific Features

Presence of high levels of MT1-MMP protein in fibroblastic cells of human invasive carcinomas

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