Characterization of the functional domain of tissue inhibitor of metalloproteinases-2 (TIMP-2)

DeClerck, Yves A.; Yean, T D; Lee, Y; Tomich, John M.; Langley, KE

doi:10.1042/bj2890065

Cited by 59 publications

(32 citation statements)

References 31 publications

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“…The HLD is known to interact with the C-terminal domain (CTD) of TIMP-2 and thus mediates the formation of proGelA/TIMP-2 complex (34,35). The N-terminal domain (NTD) of TIMP-2, on the other hand, is the inhibitory domain (36), such that TIMP-2 can bind both MT1-MMP and proGelA at the NTD and CTD, respectively. The resulting ternary complex is thought to be the same as that identified by Strongin et al (23).…”

Section: Timp-2 Promotes Processing Of Progela By Mt1-f/b-mentioning

confidence: 99%

TIMP-2 Promotes Activation of Progelatinase A by Membrane-type 1 Matrix Metalloproteinase Immobilized on Agarose Beads

Kinoshita

Sato

Okada

et al. 1998

Journal of Biological Chemistry

246

210

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Membrane-type 1 matrix metalloproteinase (MT1-MMP)/MMP-14 is the activator of progelatinase A (proGelA)/proMMP-2 on the cell surface. However, it was a paradox that a tissue inhibitor of metalloproteinase-2 (TIMP-2), which is an inhibitor of MT1-MMP, is required for proGelA activation by the cells expressing MT1-MMP. In this study, a truncated MT1-MMP having a FLAG-tag sequence at the C terminus (MT1-F) was immobilized onto agarose beads (MT1-F/B) and used to analyze the role of TIMP-2. The proteolytic activity of MT1-F/B against a synthetic peptide substrate was inhibited by TIMP-2 in a dose-dependent manner. In contrast, TIMP-2 promoted the processing of proGelA by MT1-F/B at low concentrations and inhibited it at higher concentrations. TIMP-2 promoted the binding of proGelA to the MT1-F on the beads by forming a trimolecular complex, which was followed by processing of proGelA. A stimulatory effect of TIMP-2 was observed under conditions in which unoccupied MT1-F was still available. Thus, the ternary complex is thought to act as a means to concentrate the substrate to the bead surface and to present it to the neighboring free MT1-F. Matrix metalloproteinases (MMPs)1 are zinc-dependent endopeptidases that play critical roles in the physiological and pathological turnover of extracellular matrix (ECM) by degrading the macromolecules (1-6). MMPs are produced as a zymogen (proMMP) that needs proteolytic activation by eliminating the N-terminal propeptide for the enzymes to function (7). Serine proteases such as plasmin, neutrophil elastase, and trypsin are well known activators for proMMPs. These activators digest the propeptide sequences at the basic amino acid motifs and eventually induce autocatalytic activation (8).However, proGelA lacks such a basic motif and therefore cannot be activated by serine proteinases (9). ProGelA had been reported to be activated by an unknown MMP-like activity on the surface of cancer and fibroblastic cells (10 -15), and we identified MT1-MMP as such an activator on the cell surface (16,17). Three other genes encoding similar enzymes that have a transmembrane domain and a short cytoplasmic tail were identified (18 -20); at least two of them (MT2-MMP and MT3-MMP) activated proGelA in vitro (21).Upon cell-mediated activation, proGelA binds to the cells through its hemopexin-like domain (HLD) (22). Using the HLD of GelA, Strongin et al. (23) isolated TIMP-2 complexed with the activated form of MT1-MMP from the cell membrane extract. We also purified a shaded fragment of MT1-MMP from the culture medium of the human breast carcinoma cell line MDA-MB-231 as a form inhibited by TIMP-2 (24). The Cterminal domain of the TIMP-2 in the complex was available for further complex formation with proGelA through its HLD (trimolecular complex). Strongin et al. also demonstrated that a small amount of TIMP-2 is an essential component for the activation of proGelA on the surface, in contrast to evidence that TIMP-2 is a well established inhibitor for all of the known MMPs. It would thus be of inter...

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Section: Timp-2 Promotes Processing Of Progela By Mt1-f/b-mentioning

confidence: 99%

TIMP-2 Promotes Activation of Progelatinase A by Membrane-type 1 Matrix Metalloproteinase Immobilized on Agarose Beads

Kinoshita

Sato

Okada

et al. 1998

Journal of Biological Chemistry

246

210

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“…Based on the cDNA sequence, the mature TIMP-3 protein has a predicted relative molecular mass of 21.6 x lo3 and a n estimated PI of 10.80. The mature ChIMP-3 polypeptide is also 188 amino acids long, and has a relative molecular mass of 21.8 x lo3 (Pavloff et al, 1992); the relative molecular masses of TIMP-1 and TIMP-2 are 28 x lo3 (glycosylated) and 21-23 x lo3, respectively (Docherty et al, 1985;Murphy, 1991;DeClerck et al, 1993).…”

Section: Cloning and Sequence Of The Timp-3 Cdnamentioning

confidence: 99%

Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP‐3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10

Apte

Hayashi

Seldin

et al. 1994

Developmental Dynamics

129

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Remodeling of the extracellular matrix (ECM) is an essential component of normal development and is also involved in the pathogenesis of arthritis and the spread of cancer. The matrix metalloproteinases and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play an important role in this context. We have isolated mouse cDNA clones encoding a novel member of the TIMP family, designated TIMP-3. We have assigned the Timp-3 locus to the [Cl-D11 region of mouse chromosome 10 using both genetic and cytogenetic methods. The conceptual translation product of the Timp-3 cDNA shows a high degree of similarity with ChIMP-3, a recently cloned chicken metalloproteinase inhibitor, as well as significant structural similarity with the amino acid sequences of the previously isolated members of this family, TIMP-1 and TIMP-2. The pattern of expression of Timp-3 in the developing mouse embryo is distinct from that previously reported for Timp-1. Timp-3 is expressed in cartilage and skeletal muscle, in myocardium, in the skin, oral and nasal epithelium, in the newborn mouse liver, in the epithelium of some tubular structures such as the developing bronchial tree, oesophagus, colon, urogenital sinus, bile duct, in the kidney, salivary glands, and in the choroid plexus of the brain. The patterns of Timp-3 expression in surface epithelia and in the epithelial lining of many tubular organs suggests that TIMP-3 may be involved in regulating ECM remodeling during the folding of epithelia and during the formation, branching, and expansion of epithelial tubes. In the mouse placenta, expression is seen in the trophoblast, raising the possibility that TIMP-3 may be involved in regulating trophoblastic invasion of the uterus. We propose a role for TIMP-3 in musculoskeletal and cardiac development, in the morphogenesis of certain epithelial structures, and placental implantation.

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“…Vertebrate TIMPs are known to be composed of two domains , 1991;DeClerck et al, 1993;Willenbrock et al, 1993;Ko et al, 1997;Langton et al, 1998!. Interestingly, two putative C. elegans proteins consist of only an NTR domain~Fig.…”

mentioning

confidence: 99%

The NTR module: Domains of netrins, secreted frizzled related proteins, and type I procollagen C‐proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases

1999

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Using homology search, structure prediction, and structural characterization methods we show that the C-terminal domains of~1! netrins,~2! complement proteins C3, C4, C5,~3! secreted frizzled-related proteins, and~4! type I procollagen C-proteinase enhancer proteins~PCOLCEs! are homologous with the N-terminal domains of~5! tissue inhibitors of metalloproteinases~TIMPs!. The proteins harboring this netrin module~NTR module! fulfill diverse biological roles ranging from axon guidance, regulation of Wnt signaling, to the control of the activity of metalloproteases. With the exception of TIMPs, it is not known at present what role the NTR modules play in these processes. In view of the fact that the NTR modules of TIMPs are involved in the inhibition of matrixin-type metalloproteases and that the NTR module of PCOLCEs is involved in the control of the activity of the astacin-type metalloprotease BMP1, it seems possible that interaction with metzincins could be a shared property of NTR modules and could be critical for the biological roles of the host proteins.

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Characterization of the functional domain of tissue inhibitor of metalloproteinases-2 (TIMP-2)

Cited by 59 publications

References 31 publications

TIMP-2 Promotes Activation of Progelatinase A by Membrane-type 1 Matrix Metalloproteinase Immobilized on Agarose Beads

TIMP-2 Promotes Activation of Progelatinase A by Membrane-type 1 Matrix Metalloproteinase Immobilized on Agarose Beads

Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP‐3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10

The NTR module: Domains of netrins, secreted frizzled related proteins, and type I procollagen C‐proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases

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