Delineating the Molecular Basis of the Inactivity of Tissue Inhibitor of Metalloproteinase-2 against Tumor Necrosis Factor-α-converting Enzyme

Lee, Meng-Huee; Rapti, Magdalini; Murphy, Gillian

doi:10.1074/jbc.m406611200

Cited by 31 publications

(41 citation statements)

References 26 publications

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“…As regards its activation, furin-like proprotein convertases remove the latency-maintaining propeptide domain of ADAM17 during its transit through the trans-Golgi network, thus rendering ADAM17 fully active at the cell surface [65]. As already noted, the only known inhibitor of ADAM17-TIMP3 [48]-is specifically downregulated in and around invading TEBs (but not trailing ducts). Thus, even though ADAM17 is ubiquitously expressed and activated, the local downregulation of its sole inhibitor would tend to enhance its net activity in an apt location.…”

Section: What Cues Act Upstream Of the Adam17-areg-egfr Axis?mentioning

confidence: 86%

“…Moreover, TIMP1 transcript levels were significantly higher in TEBs than in ducts, whereas TIMP3 levels were significantly lower in TEBs than in ducts, further suggesting that TIMP1 is specifically upregulated in actively developing TEBs, while TIMP3 is specifically downregulated. Because TIMP3 is the sole endogenous inhibitor of ADAM17 [48], this inverse regulation of TIMP1 and TIMP3 in TEBs would tend to de-constrain ADAM17 and increase its net proteolytic activity in an area of active ductal invasion and branching, while at the same time limiting the activity of other TIMP1-inhibitable ADAMs. Thus, given its ability to process AREG in culture and its documented importance in other EGFR-dependent processes, ADAM17 seemed the most likely candidate to be responsible for AREG-mediated EGFR activation in mammary development.…”

Section: Epithelial Adam17 Is Required For Mammary Developmentmentioning

confidence: 99%

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The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra-and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17-AREG-EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.

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Section: What Cues Act Upstream Of the Adam17-areg-egfr Axis?mentioning

confidence: 86%

Section: Epithelial Adam17 Is Required For Mammary Developmentmentioning

confidence: 99%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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“…TIMP-1 is a very poor inhibitor of MT1-MMP, MMP-19 and ADAM17, but it gains reactivity for all three metalloproteinases by replacing Thr98 with Leu, along with modifications to the AB loop [98]. TIMP-2 which does not inhibit ADAM17 may be converted to a functional inhibitor by replacing the AB loop with that of with TIMP-3, in combination with S2T/A70S/V71L mutations [99]. Full-length TIMP-4 is a weak inhibitor of ADAM17, but truncation of the C-terminal domain increased the reactivity.…”

Section: Inhibition Mechanism Of Timps and Timp Variantsmentioning

confidence: 99%

Structure and function of matrix metalloproteinases and TIMPs

Nagase

Visse

Murphy

2006

Cardiovascular Research

2,820

2,484

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Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They play central roles in morphogenesis, wound healing, tissue repair and remodelling in response to injury, e.g. after myocardial infarction, and in progression of diseases such as atheroma, arthritis, cancer and chronic tissue ulcers. They are multi-domain proteins and their activities are regulated by tissue inhibitors of metalloproteinases (TIMPs). This review introduces the members of the MMP family and discusses their domain structure and function, proenyme activation, the mechanism of inhibition by TIMPs and their significance in physiology and pathology.

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“…Production, Refolding, and Activity Assessment of Full-length and N-TIMP-4 -The protocols for the production, refolding, and titration of full-length and N-TIMP-4 were almost identical to those of N-TIMP-2 elaborated in our previous papers with the exception that 0.6 M Larginine was included in the refolding solution (17,18). The concentration of active TIMPs in each preparation was determined by titration against a known amount of gelatinase-A (MMP-2) and/or collagenase-3 (MMP-13) as described before (19).…”

Section: Methodsmentioning

confidence: 99%

“…Vent DNA polymerase for mutagenesis and the restriction enzymes for subcloning were obtained from New England Biolabs (Hitchin, Hertfordshire, UK). The fluorescent substrate for TACE assay ((7-methoxycoumarin-4-yl)-acetyl-Ser-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Arg-Lys-2,4-dinitrophenyl-NH 2 ) was synthesized and purified by Dr. Graham Knight, Department of Biochemistry, University of Cambridge, as reported in our early papers (17,18 ) were amplified from the human cDNA template by PCR before being subcloned into the E. coli expression plasmid pRSET-c (Invitrogen). A hexahistidine tag was added to the C termini of the TIMP-4 constructs during PCR amplification for the ease of downstream purification.…”

Section: Methodsmentioning

confidence: 99%

Total Conversion of Tissue Inhibitor of Metalloproteinase (TIMP) for Specific Metalloproteinase Targeting

Lee

Rapti

Murphy

2005

Journal of Biological Chemistry

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Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the matrix metalloproteinases, the ADAMs (a disintegrin and metalloproteinase) and the ADAM-TS (ADAM with thrombospondin repeats) proteinases. There are four mammalian TIMPs (TIMP-1 to -4), and each TIMP has its own profile of metalloproteinase inhibition. TIMP-4 is the latest member of the TIMPs to be cloned, and it has never been reported to be active against the tumor necrosis factor-␣-converting enzyme (TACE, ADAM-17). Here we examined the inhibitory properties of the full-length and the N-terminal domain form of TIMP-4 (N-TIMP-4) with TACE and showed that N-TIMP-4 is a far superior inhibitor than its full-length counterpart. Although fulllength TIMP-4 displayed negligible activity against TACE, N-TIMP-4 is a slow tight-binding inhibitor with low nanomolar binding affinity. Our findings suggested that the C-terminal subdomains of the TIMPs have a significant impact over their activities with the ADAMs. To elucidate further the molecular basis that underpins TIMP/TACE interactions, we sculpted N-TIMP-4 with the surface residues of TIMP-3, the only native TIMP inhibitor of the enzyme. Transplantation of only three residues, Pro-Phe-Gly, onto the AB-loop of N-TIMP-4 resulted in a 10-fold enhancement in binding affinity; the K i values of the resultant mutant were almost comparable with that of TIMP-3. Further mutation at the EF-loop supported our earlier findings on the preference of TACE for leucine at this locus. Drawing together our previous experience in TACE-targeted mutagenesis by using TIMP-1 and -2 scaffolds, we have finally resolved the mystery of the selective sensitivity of TACE to TIMP-3. Tissue inhibitor of metalloproteinases (TIMP(s))1 are the endogenous regulators of the zinc-dependent metalloproteinases (MPs) of the matrix metalloproteinase (MMP), the ADAM (a disintegrin and metalloproteinase), and the ADAM-TS (ADAMs with thrombospondin repeats) families. There are four mammalian TIMPs identified to date (TIMP-1 to -4), and they are all small molecules of ϳ24 kDa in molecular mass. The TIMPs are 40 -50% identical in amino acid sequence (reviewed in Ref. 1), and structural analysis reveals that the molecules are composed of two very distinct N-and C-terminal domains. The N-terminal domain (N-TIMP) encompasses nearly the first two-thirds of the polypeptide, and the domain is made up of five-stranded pleated sheets in the shape of a conical ␤-barrel. The tertiary configuration of the domain is typical of that of an oligonucleotide/oligosaccharide-binding motif (2-4). It is within the N-terminal domain that the inhibitory activity of a TIMP resides. The C-terminal domain is ϳ8 kDa in mass. In contrast to the N terminus, this domain is less well defined (3, 5). There are three disulfide bonds in each domain, but only the full-length and the N-terminal forms of TIMPs have been expressed so far and refolded from Escherichia coli inclusion bodies (6 -10). No success has yet been achieved in expressing the C terminus as an i...

show abstract

Delineating the Molecular Basis of the Inactivity of Tissue Inhibitor of Metalloproteinase-2 against Tumor Necrosis Factor-α-converting Enzyme

Cited by 31 publications

References 26 publications

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Structure and function of matrix metalloproteinases and TIMPs

Total Conversion of Tissue Inhibitor of Metalloproteinase (TIMP) for Specific Metalloproteinase Targeting

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