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

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A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10. / Parkin, Edward; Harris, Benjamin.

In: Journal of Neurochemistry, Vol. 108, No. 6, 03.2009, p. 1464-1479.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

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Parkin E, Harris B. A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10. Journal of Neurochemistry. 2009 Mar;108(6):1464-1479. doi: 10.1111/j.1471-4159.2009.05907.x

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Parkin, Edward ; Harris, Benjamin. / A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10. In: Journal of Neurochemistry. 2009 ; Vol. 108, No. 6. pp. 1464-1479.

Bibtex

@article{f4a2c9a3aa284e0aa3931c8a7cc8a5e1,
title = "A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10",
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.",
keywords = "ADAM Proteins, Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Arginine, Cell Line, Disintegrins, Enzyme Inhibitors, Humans, Membrane Proteins, Metalloproteases, Mutation, Neuroblastoma, Peptides, Phosphoinositide Phospholipase C, Protein Structure, Tertiary, Protein Transport, RNA, Small Interfering, Tetradecanoylphorbol Acetate, Transfection",
author = "Edward Parkin and Benjamin Harris",
year = "2009",
month = mar,
doi = "10.1111/j.1471-4159.2009.05907.x",
language = "English",
volume = "108",
pages = "1464--1479",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "6",

}

RIS

TY - JOUR

T1 - A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10

AU - Parkin, Edward

AU - Harris, Benjamin

PY - 2009/3

Y1 - 2009/3

N2 - 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.

AB - 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.

KW - ADAM Proteins

KW - Amyloid Precursor Protein Secretases

KW - Amyloid beta-Protein Precursor

KW - Arginine

KW - Cell Line

KW - Disintegrins

KW - Enzyme Inhibitors

KW - Humans

KW - Membrane Proteins

KW - Metalloproteases

KW - Mutation

KW - Neuroblastoma

KW - Peptides

KW - Phosphoinositide Phospholipase C

KW - Protein Structure, Tertiary

KW - Protein Transport

KW - RNA, Small Interfering

KW - Tetradecanoylphorbol Acetate

KW - Transfection

UR - http://www.scopus.com/inward/record.url?scp=61349132079&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2009.05907.x

DO - 10.1111/j.1471-4159.2009.05907.x

M3 - Journal article

C2 - 19183255

VL - 108

SP - 1464

EP - 1479

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 6

ER -