| Thiol isomerases negatively regulate the cellular shedding activity of ADAM17. | |
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MedLine Citation:
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PMID: 20345372 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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ADAM17 (where ADAM is 'a disintegrin and metalloproteinase') can rapidly modulate cell-surface signalling events by the proteolytic release of soluble forms of proligands for cellular receptors. Many regulatory pathways affect the ADAM17 sheddase activity, but the mechanisms for the activation are still not clear. We have utilized a cell-based ADAM17 assay to show that thiol isomerases, specifically PDI (protein disulfide isomerase), could be responsible for maintaining ADAM17 in an inactive form. Down-regulation of thiol isomerases, by changes in the redox environment (for instance as elicited by phorbol ester modulation of mitochondrial reactive oxygen species) markedly enhanced ADAM17 activation. On the basis of ELISA binding studies with novel fragment antibodies against ADAM17 we propose that isomerization of the disulfide bonds in ADAM17, and the subsequent conformational changes, form the basis for the modulation of ADAM17 activity. The shuffling of disulfide bond patterns in ADAMs has been suggested by a number of recent adamalysin crystal structures, with distinct disulfide bond patterns altering the relative orientations of the domains. Such a mechanism is rapid and reversible, and the role of thiol isomerases should be investigated further as a potential factor in the redox regulation of ADAM17. |
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Authors:
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Sofie H Willems; Christopher J Tape; Peter L Stanley; Neil A Taylor; Ian G Mills; David E Neal; John McCafferty; Gillian Murphy |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-27 |
Journal Detail:
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Title: The Biochemical journal Volume: 428 ISSN: 1470-8728 ISO Abbreviation: Biochem. J. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-27 Completed Date: 2010-07-23 Revised Date: 2010-09-22 |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: England |
Other Details:
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Languages: eng Pagination: 439-50 Citation Subset: IM |
Affiliation:
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Department of Oncology, Cambridge University, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB20RE, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ADAM Proteins
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genetics,
metabolism* Cell Line, Tumor Down-Regulation* Hela Cells Humans Protein Disulfide-Isomerases / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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//Cancer Research UK |
| Chemical | |
Reg. No./Substance:
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EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/tumor necrosis factor-alpha convertase; EC 5.3.4.1/Protein Disulfide-Isomerases |
| Comments/Corrections | |
Comment In:
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Biochem J. 2010 Jun 15;428(3):e3-5
[PMID:
20504280
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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