Structural features and biochemical properties of TNF-α converting enzyme (TACE)

Moss, Marcia L.; Jin, Shijie; Becherer, J. David; Bickett, D. Mark; Burkhart, William; Chen, W.-J.; Hassler, Daniel F.; Leesnitzer, M.T.; McGeehan, Gerard M.; Milla, Marcos E.; Moyer, Mary B.; Rocque, Warren J.; Seaton, Theresa; Schoenen, Frank J.; Warner, Janet; Willard, Derril H.

doi:10.1016/s0165-5728(96)00180-4

Cited by 106 publications

(79 citation statements)

References 12 publications

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“…TACE/ADAM17 was originally identified by its ability to cleave transmembrane TNF-α to soluble TNF-α in THP-1 cells (Black et al, 1997;Moss et al, 1997). Subsequently, many transmembrane proteins have been identified as substrates for this enzyme, e.g.…”

Section: Introductionmentioning

confidence: 99%

ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking

Soond

Everson

Riches

et al. 2005

Journal of Cell Science

212

216

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Tumor necrosis factor α-converting enzyme (TACE/ADAM17) has been implicated in the inducible shedding of numerous cell surface proteins. In light of this, the regulation of TACE catalytic activation and protein maturation has recently received considerable interest in the context of extracellular signal-regulated kinase activation and the subsequent phosphorylation of TACE at residue Thr735. In this study, we analysed the subcellular localisation of TACE derivatives using laser-scanning confocal microscopy and cell surface biotinylation. Whereas WT.TACE- and T735A.TACE-enhanced green fluorescent protein (-eGFP) fusion derivatives of TACE were both found to localise with the endoplasmic reticulum, a phosphomimicking form of TACE (T735E.TACE-eGFP) was found to colocalise predominantly with components of the protein secretory pathway (COPII vesicles and trans-Golgi network). Additionally, upon analysis of biotinylated ectopic TACE, we observed that inducible trafficking of TACE to the cell surface was dependent upon extracellular signal-regulated kinase activation and phosphorylation of Thr735. We conclude from our observations that phosphorylation of TACE at Thr735 highlights a key step in inducible TACE protein trafficking and maturation.

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Section: Introductionmentioning

confidence: 99%

ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking

Soond

Everson

Riches

et al. 2005

Journal of Cell Science

212

216

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“…Thus, surface localization may serve to restrict activity to specific microenvironments, whereas release may lead to distal effects. TNF is synthesized as a 26 kDa type II transmembrane molecule, which can be processed by a TNF-alpha converting enzyme (TACE or ADAM17), to generate secreted 17 kDa monomers that form biologically active homotrimers [11,12]. Indications for a role of tmTNF in vivo have been obtained in genetically modified Tg mice.…”

Section: Introductionmentioning

confidence: 99%

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

et al. 2006

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Using targeted mutagenesis in mice, we have blocked shedding of endogenous murine TNF by deleting its cleavage site. Mutant mice produce physiologically regulated levels of transmembrane TNF (tmTNF), which suffice to support thymocyte proliferation but cannot substitute for the hepatotoxic activities of wild-type TNF following LPS/Dgalactosamine challenge in vivo and are not sufficient to support secondary lymphoid organ structure and function. Notably, however, tmTNF is capable of exerting antiListerial host defenses while remaining inadequate to mediate arthritogenic functions, as tested in the tristetraprolin-deficient model of TNF-dependent arthritis. Most interestingly, in the EAE model of autoimmune demyelination, tmTNF suppresses disease onset and progression and retains the autoimmune suppressive properties of wild-type TNF. Together, these results indicate that tmTNF preserves a subset of the beneficial activities of TNF while lacking detrimental effects. These data support the hypothesis that selective targeting of soluble TNF may offer several advantages over complete blockade of TNF in the treatment of chronic inflammation and autoimmunity.Supporting information for this article is available at: http://www.wiley-vch.de/contents/jc_2040/2006/35921_s.pdf IntroductionOriginally identified as an endotoxin-induced serum factor that causes necrosis of tumors [1] and/or cachexia [2], TNF is currently known to mediate a wide array of biological activities [3, 4]. TNF is produced in response to bacterial toxins, inflammatory products and other stimuli mainly by cells of the myeloid lineage, with additional producers including B and T lymphocytes, NK cells, microglia, astrocytes and adipocytes [3]. TNF is bioactive both as a transmembrane protein and as a homotrimeric secreted molecule [5] and mediates its effects through two distinct TNF receptors, p55TNFR (TNFRI) and p75TNFR (TNFRII) [6]. Transmembrane TNF (tmTNF) appears superior to soluble TNF in activating the p75TNFR, while at physiological concentrations soluble TNF primarily activates the p55TNFR [7]. The two types of TNF receptors share structural homology in the extracellular TNF-binding domains, but they induce separate cytoplasmic signaling pathways following receptor-ligand interaction [8]. Apoptosis and activation of NF-jB are initiated by p55TNFR, whereas p75TNFR appears to play a direct role in only a limited number of TNF responses [6,9]. Several functionally diverse proteins, such as growth factors and cytokines and including TNF, are initially synthesized as biologically active membrane-anchored molecules that are subsequently released from the cell by proteolysis [10]. Thus, surface localization may serve to restrict activity to specific microenvironments, whereas release may lead to distal effects. TNF is synthesized as a 26 kDa type II transmembrane molecule, which can be processed by a TNF-alpha converting enzyme (TACE or ADAM17), to generate secreted 17 kDa monomers that form biologically active homotrimers [11,12]. Indications for a r...

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“…The ␣-secretase TACE/ADAM17 (or tumor necrosis factor-␣-converting enzyme) is a metalloprotease that was pri-marily identified by its ability to cleave the proinflammatory cytokine TNF␣ (15,16). TACE/ADAM17 proteolytic activity releases by "ectodomain shedding" functional domains from a growing list of membrane-anchored substrates including the Notch receptor, the epidermal growth factor receptor, the amyloid precursor protein (APP), and other cytokine receptors and adhesion receptors (for review, see Ref.…”

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confidence: 99%

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

Bot

Schweizer

Halima³

et al. 2011

Journal of Biological Chemistry

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Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding across the synaptic cleft of the ectodomains of presynaptic NRXNs and postsynaptic neuroligins have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that ␣-and ␥-secretases can sequentially process NRXN3␤, leading to the formation of two final products, an ϳ80-kDa N-terminal extracellular domain of Neurexin-3␤ (sNRXN3␤) and an ϳ12-kDa C-terminal intracellular NRXN3␤ domain (NRXN3␤-ICD), both of them being potentially implicated in the regulation of NRXNs and neuroligins functions at the synapses or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the ␥-secretase that cause early-onset familial Alzheimer disease.

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Structural features and biochemical properties of TNF-α converting enzyme (TACE)

Cited by 106 publications

References 12 publications

ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking

ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking

Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

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