TY  - JOUR
AU  - Fleck, Daniel
AU  - van Bebber, Frauke
AU  - Colombo, Alessio
AU  - Galante, Chiara
AU  - Schwenk, Benjamin M
AU  - Rabe, Linnea
AU  - Hampel, Heike
AU  - Novak, Bozidar
AU  - Kremmer, Elisabeth
AU  - Tahirovic, Sabina
AU  - Edbauer, Dieter
AU  - Lichtenthaler, Stefan F
AU  - Schmid, Bettina
AU  - Willem, Michael
AU  - Haass, Christian
TI  - Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling.
JO  - The journal of neuroscience
VL  - 33
IS  - 18
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.57413
M1  - DZNE-2020-03214
SP  - 7856-7869
PY  - 2013
AB  - 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.
KW  - ADAM Proteins: metabolism
KW  - ADAM17 Protein
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Animals
KW  - Aspartic Acid Endopeptidases: metabolism
KW  - Cell Membrane: metabolism
KW  - Cells, Cultured
KW  - Cricetinae
KW  - Cricetulus
KW  - Embryo, Mammalian
KW  - Epidermal Growth Factor: analogs & derivatives
KW  - Epidermal Growth Factor: chemistry
KW  - Humans
KW  - Immunoprecipitation
KW  - Neuregulins: genetics
KW  - Neuregulins: metabolism
KW  - Neurons
KW  - Paracrine Communication: physiology
KW  - Phosphorylation
KW  - Proteolysis
KW  - RNA, Messenger: administration & dosage
KW  - RNA, Messenger: metabolism
KW  - RNA, Small Interfering: metabolism
KW  - Rats
KW  - Rats, Sprague-Dawley
KW  - Schwann Cells
KW  - Transfection
KW  - Zebrafish
KW  - NRG3 protein, human (NLM Chemicals)
KW  - Neuregulins (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - Epidermal Growth Factor (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - BACE1 protein, human (NLM Chemicals)
KW  - ADAM Proteins (NLM Chemicals)
KW  - ADAM17 Protein (NLM Chemicals)
KW  - ADAM17 protein, human (NLM Chemicals)
KW  - Adam17 protein, rat (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23637177
C2  - pmc:PMC6618983
DO  - DOI:10.1523/JNEUROSCI.3372-12.2013
UR  - https://pub.dzne.de/record/136892
ER  -