Functional Analysis of the Domain Structure of Tumor Necrosis Factor-α Converting Enzyme

Many membrane-bound proteins, including cytokines, receptors, and growth factors, are proteolytically cleaved to release a soluble form of their extracellular domain. The tumor necrosis factor (TNF)-α converting enzyme (TACE/ADAM-17) is a transmembrane metalloproteinase responsible for the proteolyt...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-05, Vol.275 (19), p.14608-14614
Main Authors: Reddy, Pranhitha, Slack, Jennifer L., Davis, Raymond, Cerretti, Douglas Pat, Kozlosky, Carl J., Blanton, Rebecca A., Shows, Donna, Peschon, Jacques J., Black, Roy A.
Format: Article
Language:English
Subjects:
ADAM Proteins
ADAM17 Protein
Animals
Antigens, CD - metabolism
Catalytic Domain
Cell Line
Cytoplasm - enzymology
DNA, Complementary
Metalloendopeptidases - antagonists & inhibitors
Metalloendopeptidases - chemistry
Metalloendopeptidases - genetics
Metalloendopeptidases - metabolism
Mice
Receptors, Tumor Necrosis Factor - metabolism
Receptors, Tumor Necrosis Factor, Type II
Transfection
tumor necrosis factor-^a converting enzyme
Tumor Necrosis Factor-alpha - metabolism
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Summary:Many membrane-bound proteins, including cytokines, receptors, and growth factors, are proteolytically cleaved to release a soluble form of their extracellular domain. The tumor necrosis factor (TNF)-α converting enzyme (TACE/ADAM-17) is a transmembrane metalloproteinase responsible for the proteolytic release or “shedding” of several cell-surface proteins, including TNF and p75 TNFR. We established a TACE-reconstitution system using TACE-deficient cells co-transfected with TACE and substrate cDNAs to study TACE function and regulation. Using the TACE-reconstitution system, we identified two additional substrates of TACE, interleukin (IL)-1R-II and p55 TNFR. Using truncations and chimeric constructs of TACE and another ADAM family member, ADAM-10, we studied the function of the different domains of TACE in three shedding activities. We found that TACE must be expressed with its membrane-anchoring domain for phorbol ester-stimulated shedding of TNF, p75 TNFR, and IL-1R-II, but that the cytoplasmic domain is not required for the shedding of these substrates. The catalytic domain of ADAM-10 could not be functionally substituted for that of TACE. IL-1R-II shedding required the cysteine-rich domain of TACE as well as the catalytic domain, whereas TNF and p75 TNFR shedding required only the tethered TACE catalytic domain.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.275.19.14608