A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10

Parkin, Edward and Harris, Benjamin (2009) A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10. Journal of Neurochemistry, 108 (6). pp. 1464-1479. ISSN 1471-4159

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Abstract

A disintegrin and metalloproteinase (ADAM) 10 is a type I transmembrane glycoprotein responsible for the ectodomain shedding of a range of proteins including the amyloid precursor protein implicated in Alzheimer's disease. In this study we demonstrate that ADAM10 itself is subject to shedding by one or more ADAMs. Expression of epitope-tagged wild-type ADAM10 in SH-SY5Y cells enabled the detection of a soluble ectodomain in conditioned medium. Shedding of the ADAM10 ectodomain was inhibited by a known ADAM inhibitor with a reciprocal accumulation of the full-length mature protein in both cell lysates and extracellular membrane vesicles. Shedding was also stimulated by phorbol ester treatment of cells. A glycosylphosphatidylinositol-anchored form of ADAM10 lacking the cytosolic, transmembrane and alpha-helical juxtamembrane regions of the wild-type protein was shed in a similar manner. Furthermore, a truncated soluble ADAM10 construct, although correctly post-translationally processed and catalytically active against a synthetic peptide substrate, was incapable of shedding cell-associated amyloid precursor protein. Finally, we show that ADAM9 is, at least in part, responsible for the ectodomain shedding of ADAM10. In conclusion, this is a new mechanism by which levels of ADAM10 are regulated and may have implications in a range of human diseases including Alzheimer's disease.

Item Type:
Journal Article
Journal or Publication Title:
Journal of Neurochemistry
Uncontrolled Keywords:
/dk/atira/pure/core/keywords/biologicalsciences/biomedicalandlifesciences
Subjects:
?? adam proteinsamyloid precursor protein secretasesamyloid beta-protein precursorargininecell linedisintegrinsenzyme inhibitorshumansmembrane proteinsmetalloproteasesmutationneuroblastomapeptidesphosphoinositide phospholipase cprotein structure, tertiarypro ??
ID Code:
51850
Deposited By:
Deposited On:
06 Dec 2011 16:21
Refereed?:
Yes
Published?:
Published
Last Modified:
15 Jul 2024 12:33