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Fleck, D.* ; van Bebber, F.* ; Colombo, A.* ; Galante, C.* ; Schwenk, B.M.* ; Rabe, L.* ; Hampel, H.* ; Novak, B.* ; Kremmer, E. ; Tahirovic, S.* ; Edbauer, D.* ; Lichtenthaler, S.F.* ; Schmid, B.* ; Willem, M.* ; Haass, C.*

Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling.

J. Neurosci. 33, 7856-7869 (2013)
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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 beta-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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Regulated Intramembrane Proteolysis ; Amyloid Precursor Protein ; Schwann-cell Myelination ; Necrosis-factor-alpha ; Nervous-system ; Beta-secretase ; Alzheimers-disease ; Ectodomain ; Isoforms ; Schizophrenia
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0270-6474
e-ISSN 1529-2401
Zeitschrift Journal of Neuroscience
Quellenangaben Band: 33, Heft: 18, Seiten: 7856-7869 Artikelnummer: , Supplement: ,
Verlag Society for Neuroscience
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Immunology (IMI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501793-001
PubMed ID 23637177
DOI 10.1523/JNEUROSCI.3372-12.2013
WOS ID WOS:000318420400023
Scopus ID 84877125044
Erfassungsdatum 2013-06-06
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