TNFα converting enzyme

Moss, Marcia L.; Becherer, J. David; Milla, Marcos E.; Pahel, Gregory; Lambert, Mill H.; Andrews, Robert J.; Frye, Stephen V.; Haffner, Curt D.; Cowan, David J.; Maloney, Patrick; Dixon, Eric P.; Jansen, Marilyn; Vitek, Michael P.; Mitchell, Justin; Leesnitzer, Tony; Warner, Janet; Conway, James G.; Bickett, D. Mark; Bird, Michael R.; Priest, Richard; Reinhard, John F.; Lin, Psang Dain

doi:10.1007/978-3-0348-8666-6_9

Cited by 7 publications

(2 citation statements)

References 38 publications

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“…2 Pradines-Figueres and Raetz (24) have shown that TNF␣ secretion from MonoMac 6 cells occurs only after stimulation of these cells with both bacterial lipopolysaccharide and phorbol-12-myristate-13-acetate. Although proTNF␣ biosynthesis is enhanced after lipopolysaccharide stimulation, release does not occur to significant levels in the absence of phorbol 12-myristate 13-acetate (13). Potentially, a phorbol 12-myristate 13-acetate-initiated phosphorylation or dephosphorylation event at the cytosolic tail of TACE precedes TACE activation, either via a conformational change that exposes the cleavage site to the processing protease(s) or by directing transport of TACE to the compartment where activation takes place.…”

Section: Discussionmentioning

confidence: 99%

“…Its sequence corresponds to the cleavage site of TACE on proTNF␣. The ratio of product versus substrate was determined by measuring the absorbance at 370 nm of the correspondent peaks after HPLC separation of the reaction mixture using a C18 column (13). Activity was also measured against recombinant proTNF␣ by a gel-shift assay based on the substantial difference in mobility of the substrate (26 kDa) and products (17 and 9 kDa) in 12% denaturing SDS-polyacrylamide gels.…”

Section: Methodsmentioning

confidence: 99%

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Specific Sequence Elements Are Required for the Expression of Functional Tumor Necrosis Factor-α-converting Enzyme (TACE)

Milla

Leesnitzer

Moss

et al. 1999

Journal of Biological Chemistry

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152

156

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The tumor necrosis factor-␣-converting enzyme (TACE) is a membrane-anchored zinc metalloprotease involved in precursor tumor necrosis factor-␣ secretion. We designed a series of constructs containing full-length human TACE and several truncate forms for overexpression in insect cells. Here, we demonstrate that fulllength TACE is expressed in insect cells inefficiently: only minor amounts of this enzyme are converted from an inactive precursor to the mature, functional form. Removal of the cytoplasmic and transmembrane domains resulted in the efficient secretion of mature, active TACE. Further removal of the cysteine-rich domain located between the catalytic and transmembrane domains resulted in the secretion of mature catalytic domain in association with the precursor (pro) domain. This complex was inactive and function was only restored after dissociation of the complex by dilution or treatment with 4-aminophenylmercuric acetate. Therefore, the pro domain of TACE is an inhibitor of the catalytic domain, and the cysteine-rich domain appears to play a role in the release of the pro domain. Insect cells failed to secrete a deletion mutant encoding the catalytic domain but lacking the inhibitory pro domain. This truncate was inactive and extensively degraded intracellularly, suggesting that the pro domain is required for the secretion of functional TACE. TNF␣1 is a potent cytokine that is secreted by activated monocytes and macrophages in a tightly regulated manner (1). Upon release, TNF␣ mediates the recruitment and activation of inflammatory cells to injured or infected tissues (2). Elevated levels of circulating TNF␣ have been demonstrated in several acute and chronic pathological states, such as lipopolysaccharide-induced septic shock, arthritis, pleurisy, Crohn's disease, and inflammatory bowel disease (3). TNF␣ is synthesized as a pro, membrane-anchored form facing the lumenal/extracellular side of the secretory pathway. Our group and others have shown that proTNF␣ is released from cells after endoproteolytic cleavage at positions Ala 76 -Val 77 , mediated by a zinc metalloprotease sensitive to hydroxamic acid inhibitors (4 -6). Because neutralization of TNF␣ activity has been demonstrated in the clinic, this enzyme constitutes a potential target for drug discovery.The TNF␣-converting enzyme (TACE) was purified to homogeneity and cloned (7,8). Analysis of its amino acid sequence demonstrates a multidomain protein closely resembling members of the disintegrin family of metalloproteases, also commonly referred to as ADAMs or metalloprotease and disintegrin-containing proteins (9). Starting at the N terminus, TACE exhibits a classical signal peptide followed by a ϳ200-residue pro domain that includes a consensus cysteine switch motif (PKVCGY 186 ), which can act as an inhibitor by ligating the zinc ion in the catalytic site (10, 32). The catalytic domain starts downstream from a consensus furin cleavage site (RVKRR 215 ) and contains a canonical zinc binding site and a MYP loop involved in formation of the P1Ј p...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Specific Sequence Elements Are Required for the Expression of Functional Tumor Necrosis Factor-α-converting Enzyme (TACE)

Milla

Leesnitzer

Moss

et al. 1999

Journal of Biological Chemistry

Self Cite

152

156

View full text Add to dashboard Cite

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Neuronal localization of the TNFα converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques

et al. 2001

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The tumor necrosis factor (TNF)-alpha converting enzyme (TACE) can cleave the cell-surface ectodomain of the amyloid-beta precursor protein (APP), thus decreasing the generation of amyloid-beta (Abeta) by cultured non-neuronal cells. While the amyloidogenic processing of APP in neurons is linked to the pathogenesis of Alzheimer's disease (AD), the expression of TACE in neurons has not yet been examined. Thus, we assessed TACE expression in a series of neuronal and non-neuronal cell types by Western blots. We found that TACE was present in neurons and was only faintly detectable in lysates of astrocytes, oligodendrocytes, and microglial cells. Immunohistochemical analysis was used to determine the cellular localization of TACE in the human brain, and its expression was detected in distinct neuronal populations, including pyramidal neurons of the cerebral cortex and granular cell layer neurons in the hippocampus. Very low levels of TACE were seen in the cerebellum, with Purkinje cells at the granular-molecular boundary staining faintly. Because TACE was localized predominantly in areas of the brain that are affected by amyloid plaques in AD, we examined its expression in a series of AD brains. We found that AD and control brains showed similar levels of TACE staining, as well as similar patterns of TACE expression. By double labeling for Abeta plaques and TACE, we found that TACE-positive neurons often colocalized with amyloid plaques in AD brains. These observations support a neuronal role for TACE and suggest a mechanism for its involvement in AD pathogenesis as an antagonist of Abeta formation.

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ADAM 17 endopeptidase

2009

Class 3 Hydrolases

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TNFα converting enzyme

Cited by 7 publications

References 38 publications

Specific Sequence Elements Are Required for the Expression of Functional Tumor Necrosis Factor-α-converting Enzyme (TACE)

Specific Sequence Elements Are Required for the Expression of Functional Tumor Necrosis Factor-α-converting Enzyme (TACE)

Neuronal localization of the TNFα converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques

ADAM 17 endopeptidase

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