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@ARTICLE{Fleck:136892,
author = {Fleck, Daniel and van Bebber, Frauke and Colombo, Alessio
and Galante, Chiara and Schwenk, Benjamin M and Rabe, Linnea
and Hampel, Heike and Novak, Bozidar and Kremmer, Elisabeth
and Tahirovic, Sabina and Edbauer, Dieter and Lichtenthaler,
Stefan F and Schmid, Bettina and Willem, Michael and Haass,
Christian},
title = {{D}ual cleavage of neuregulin 1 type {III} by {BACE}1 and
{ADAM}17 liberates its {EGF}-like domain and allows
paracrine signaling.},
journal = {The journal of neuroscience},
volume = {33},
number = {18},
issn = {0270-6474},
address = {Washington, DC},
publisher = {Soc.57413},
reportid = {DZNE-2020-03214},
pages = {7856-7869},
year = {2013},
abstract = {Proteolytic shedding of cell surface proteins generates
paracrine signals involved in numerous signaling pathways.
Neuregulin 1 (NRG1) type III is involved in myelination of
the peripheral nervous system, for which it requires
proteolytic activation by proteases of the ADAM family and
BACE1. These proteases are major therapeutic targets for the
prevention of Alzheimer's disease because they are also
involved in the proteolytic generation of the neurotoxic
amyloid β-peptide. Identification and functional
investigation of their physiological substrates is therefore
of greatest importance in preventing unwanted side effects.
Here we investigated proteolytic processing of NRG1 type III
and demonstrate that the ectodomain can be cleaved by three
different sheddases, namely ADAM10, ADAM17, and BACE1.
Surprisingly, we not only found cleavage by ADAM10, ADAM17,
and BACE1 C-terminal to the epidermal growth factor
(EGF)-like domain, which is believed to play a pivotal role
in signaling, but also additional cleavage sites for ADAM17
and BACE1 N-terminal to that domain. Proteolytic processing
at N- and C-terminal sites of the EGF-like domain results in
the secretion of this domain from NRG1 type III. The soluble
EGF-like domain is functionally active and stimulates ErbB3
signaling in tissue culture assays. Moreover, the soluble
EGF-like domain is capable of rescuing hypomyelination in a
zebrafish mutant lacking BACE1. Our data suggest that NRG1
type III-dependent myelination is not only controlled by
membrane-retained NRG1 type III, but also in a paracrine
manner via proteolytic liberation of the EGF-like domain.},
keywords = {ADAM Proteins: metabolism / ADAM17 Protein / Amyloid
Precursor Protein Secretases: metabolism / Animals /
Aspartic Acid Endopeptidases: metabolism / Cell Membrane:
metabolism / Cells, Cultured / Cricetinae / Cricetulus /
Embryo, Mammalian / Epidermal Growth Factor: analogs $\&$
derivatives / Epidermal Growth Factor: chemistry / Humans /
Immunoprecipitation / Neuregulins: genetics / Neuregulins:
metabolism / Neurons / Paracrine Communication: physiology /
Phosphorylation / Proteolysis / RNA, Messenger:
administration $\&$ dosage / RNA, Messenger: metabolism /
RNA, Small Interfering: metabolism / Rats / Rats,
Sprague-Dawley / Schwann Cells / Transfection / Zebrafish /
NRG3 protein, human (NLM Chemicals) / Neuregulins (NLM
Chemicals) / RNA, Messenger (NLM Chemicals) / RNA, Small
Interfering (NLM Chemicals) / Epidermal Growth Factor (NLM
Chemicals) / Amyloid Precursor Protein Secretases (NLM
Chemicals) / Aspartic Acid Endopeptidases (NLM Chemicals) /
BACE1 protein, human (NLM Chemicals) / ADAM Proteins (NLM
Chemicals) / ADAM17 Protein (NLM Chemicals) / ADAM17
protein, human (NLM Chemicals) / Adam17 protein, rat (NLM
Chemicals)},
cin = {Zebrafish Models ; AG Schmid ; AG Schmid München / AG
Lichtenthaler / AG Edbauer / AG Tahirovic / AG Haass old},
ddc = {610},
cid = {I:(DE-2719)1140002 / I:(DE-2719)1110006 /
I:(DE-2719)1110004 / I:(DE-2719)1140003 /
I:(DE-2719)1110007},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:23637177},
pmc = {pmc:PMC6618983},
doi = {10.1523/JNEUROSCI.3372-12.2013},
url = {https://pub.dzne.de/record/136892},
}