Specific, High Affinity Binding of Tissue Inhibitor of Metalloproteinases-4 (TIMP-4) to the COOH-terminal Hemopexin-like Domain of Human Gelatinase A

Bigg, Heather F.; Shi, Yuye; Liu, Yiliang E.; Steffensen, Bjørn; Overall, Christopher M.

doi:10.1074/jbc.272.24.15496

Cited by 158 publications

(120 citation statements)

References 46 publications

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“…Binding of MMP-2 to TIMP-4 was of high affinity with an apparent K d of 1.7 ϫ 10 Ϫ7 M but sightly weaker than that to TIMP-2 (apparent K d of 6.6 ϫ 10 Ϫ8 M) (43). These K d differences are in agreement with the relatively more potent inhibitory effect of TIMP-2 on MMP-2 than that of TIMP-4 (Fig.…”

Section: Figsupporting

confidence: 76%

“…A more detailed structural comparison indicated that TIMP-4 shares a relatively high identity with TIMP-2 particularly in the loops of 4 and 5 within the Cterminal domain (41). Thus, it is possible that TIMP-4 and TIMP-2 may share similar mechanistic and functional properties based on the sequence identity, similar enzymatic kinetics, and the high affinity binding to MMP-2 (43).…”

Section: Figmentioning

confidence: 99%

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Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Liu¹,

Wang²,

Greene³

et al. 1997

Journal of Biological Chemistry

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130

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MMPs 1 and their inhibitors TIMPs play a critical role in ECM homeostasis. Controlled remodeling of the ECM is an essential aspect of normal development, and deregulated remodeling has been indicated to have a role in the etiology of diseases such as arthritis, periodontal disease, and cancer metastasis (1-5). Four mammalian TIMPs have been identified so far: TIMP-1 (6), TIMP-2 (7), TIMP-3 (8 -11), and the recently cloned TIMP-4 (12, 41). The proteins are classified based on structural similarity to each other, as well as their ability to inhibit metalloproteinases.TIMPs are secreted multifunctional proteins that have anti-MMP activity as well as erythroid-potentiating and cell growth-promoting activities. The stimulating effect on cell growth was initially recognized when TIMP-1 and TIMP-2 were identified as having erythroid-potentiating activities (14,15). It is now clear through several recent reports that TIMP-1 and TIMP-2 are mitogenic for non-erythroid cells, including normal keratinocytes (16), fibroblasts (17), lung adenocarcinoma cells (18), and melanoma cells (18). The involvement of TIMPs in the activation of pro-MMP has also been demonstrated (19). In addition, the recent evidence indicates that the TIMP family may be involved in steroidogenesis of rat testis and ovary indicating the potential role of TIMP in the reproduction (20).The most widely appreciated biological function of the TIMPs is their role in the inhibition of cell invasions in vitro (21-24) and tumorigenesis (25-29) and metastasis in vivo (25-31). Since the net MMP activity is the result of the balance between activated enzyme levels and TIMP levels, an increase in the amount of TIMPs relative to MMPs could function to block tumor cell invasion and metastasis. The tumor-suppressing activity of TIMP on primary tumor growth may be in part due to its anti-angiogenic activity. In fact, both TIMP-1 (32) and TIMP-2 (33, 34) have been demonstrated to have an antiangiogenic activity, and such inhibition of angiogenesis is mediated by inhibition of both endothelial cell proliferation (34) and migration (32). The underlying molecular mechanism for the tumor suppressing activities of TIMPs, nevertheless, is thought to depend on their anti-MMP activities.We had recently cloned and characterized a human TIMP-4 (12). Transfection of TIMP-4 into human breast cancer cells inhibited the invasion potential of the cells in the in vitro invasion assay (13). When injected orthotopically into nude mice, TIMP-4 transfectants were significantly inhibited in their tumor growth and axillary lymph node and lung metastasis as compared with controls (13). These results suggest the therapeutic potential of TIMP-4 in treating cancer malignant progression. These results suggest an important role of TIMP-4 in inhibiting primary tumor growth and progression leading to invasion and metastasis. In the present study, we have produced and purified rTIMP4p from baculovirus infected cells. rTIMP4p was shown to inhibit MMP activity and tumor cell invasion across reconstitute...

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Section: Figsupporting

confidence: 76%

Section: Figmentioning

confidence: 99%

Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Liu¹,

Wang²,

Greene³

et al. 1997

Journal of Biological Chemistry

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130

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“…These results suggest that the pericellular activity of MMP-2 is tightly regulated by membrane-bound TIMP-2 and surrounding extracellular matrix components. TIMP-4 and TIMP-3 can also bind to proMMP-2 with high a nity (Butler et al, 1999;Bigg et al, 1997), but do not promote MT1-MMP mediated activation of proMMP-2 (Hernandez- Barrantes et al, 2001).…”

Section: Paradox 2: Timps Regulate Pro-mmp Activation and Tumor Angiomentioning

confidence: 99%

Complex roles of tissue inhibitors of metalloproteinases in cancer

2002

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Matrix metalloproteinases (MMPs) is tightly associated with extracellular matrix (ECM) turnover, which plays a very active role in tumor invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) plays a critical role in the homeostasis of ECM by regulating the activity of MMPs. TIMPs are well-known for their ability to inhibit MMP activity thereby inhibiting tumor growth and metastasis. However, many evidences suggest that TIMPs are multifunctional proteins, which regulate cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis. These e ects may be through MMPdependent or MMP-independent pathways. Recent data indicate that TIMPs have many paradoxical roles in tumorigenesis. In particular, both inhibitory e ect and stimulatory e ect on tumorigenesis have been demonstrated in many animal models in which TIMPs were overexpressed in cancer cells or in mice. Elevated TIMP levels are reported in association with cancer progression and identi®ed as poor prognostic indicators in several human tumor types. Herein, we review the complex roles of TIMPs in cancer growth and metastasis.

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“…The zymogenic forms of both enzymes interact, via their C-terminal domain (hemopexin-like domain), with tissue inhibitors of metalloproteinases (TIMPs), a family of specific endogenous MMP inhibitors (15,16). Pro-MMP-9 binds to TIMP-1 (1), whereas pro-MMP-2 binds to TIMP-2 (17) and to TIMP-4 (18). After activation, any TIMP molecule efficiently inhibits the enzymatic activity by binding to the catalytic domain of the MMP (16).…”

mentioning

confidence: 99%

Characterization of the Monomeric and Dimeric Forms of Latent and Active Matrix Metalloproteinase-9

Olson

Bernardo

Pietila

et al. 2000

Journal of Biological Chemistry

140

133

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Matrix metalloproteinase-9 (MMP-9) is a member of the MMP family that has been associated with degradation of the extracellular matrix in normal and pathological conditions. A unique characteristic of MMP-9 is its ability to exist in a monomeric and a disulfide-bonded dimeric form. However, there exists a paucity of information on the properties of the latent (pro-MMP-9) and active MMP-9 dimer. Here we report the purification to homogeneity of the monomer and dimer forms of pro-MMP-9 and the characterization of their biochemical properties and interactions with tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Gel filtration and surface plasmon resonance analyses demonstrated that the pro-MMP-9 monomeric and dimeric forms bind TIMP-1 with similar affinities. In contrast, TIMP-2 binds only to the active forms. After activation, the two enzyme forms exhibited equal catalytic competence in the turnover of a synthetic peptide substrate with comparable kinetic parameters for the onset of inhibition with TIMPs and for dissociation of the inhibited complexes. Kinetic analyses of the activation of monomeric and dimeric pro-MMP-9 by stromelysin 1 revealed K m values in the nanomolar range and relative low k cat values (1.9 ؋ 10 ؊3 and 4.1 ؋ 10 ؊4 s ؊1, for the monomer and dimer, respectively) consistent with a faster rate (1 order of magnitude) of activation of the monomeric form by stromelysin 1. This suggests that the rate-limiting event in the activation of pro-MMP-9 may be a requisite slow unfolding of pro-MMP-9 near the site of the hydrolytic cleavage by stromelysin 1.Matrix metalloproteinase-9 (MMP-9), 1 also known as gelatinase B, is a member of the MMP family of zinc-dependent endopeptidases known for their ability to degrade many extracellular matrix (ECM) components (1, 2). MMP-9 is secreted in a latent form (pro-MMP-9) by a variety of normal and transformed cells and has been implicated in the pathogenesis of several human diseases including arthritis (3), cardiovascular disease (4, 5), and cancer metastasis (6, 7). MMP-9 has also been suggested to play a role in the degradation of ECM during inflammation (8), wound healing (9, 10), trophoblast implantation (11), and angiogenesis (12). Structurally, pro-MMP-9 is closely related to pro-MMP-2 (gelatinase A) with both enzymes containing a fibronectin-like type II module (gelatin-binding domain) inserted into the catalytic domain that is thought to facilitate interaction of the enzymes with collagen molecules (13,14). The zymogenic forms of both enzymes interact, via their C-terminal domain (hemopexin-like domain), with tissue inhibitors of metalloproteinases (TIMPs), a family of specific endogenous MMP inhibitors (15, 16). Pro-MMP-9 binds to TIMP-1 (1), whereas pro-MMP-2 binds to TIMP-2 (17) and to TIMP-4 (18). After activation, any TIMP molecule efficiently inhibits the enzymatic activity by binding to the catalytic domain of the MMP (16).Despite the similarities that exist between pro-MMP-9 and pro-MMP-2, the former is unique in several aspects includi...

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Specific, High Affinity Binding of Tissue Inhibitor of Metalloproteinases-4 (TIMP-4) to the COOH-terminal Hemopexin-like Domain of Human Gelatinase A

Cited by 158 publications

References 46 publications

Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Complex roles of tissue inhibitors of metalloproteinases in cancer

Characterization of the Monomeric and Dimeric Forms of Latent and Active Matrix Metalloproteinase-9

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