title: Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination.
abstract: Neuregulin-1 (Nrg1) is encoded by a single gene and exists in naturally secreted and transmembrane isoforms. Nrg1 exerts its signaling activity through interaction with its cognate ErbB receptors. Multiple membrane-anchored Nrg1 isoforms, present in six different membrane topologies, must be processed by a protease to initiate a signaling cascade. Here, we demonstrate that BACE1 and ADAM10 can process type I and III Nrg1 at two adjacent sites. Our cleavage site mapping experiments showed that the BACE1 cleavage site is located eight amino acids downstream of the ADAM10 cleavage site, and this order of cleavage is the opposite of amyloid precursor protein cleavage by these two enzymes. Cleavages were further confirmed via optimized electrophoresis. Cleavage of type I or III Nrg1 by ADAM10 and BACE1 released a signaling-capable N-terminal fragment (ntf), either Nrg1-ntfα or Nrg1-ntfβ, which could similarly activate an ErbB receptor as evidenced by increased phosphorylation of Akt and ERK, two downstream signaling molecules. Although both Nrg1-ntfα and Nrg1-ntfβ could initiate a common signaling cascade, inhibition or down-regulation of ADAM10 alone in a co-culture system did not affect normal myelination, whereas specific inhibition of BACE1 impaired normal myelination. Thus, processing of Nrg1 by BACE1 appears to be more critical for regulating myelination. Our results imply that a significant inhibition of BACE1 could potentially impair Nrg1 signaling activity in vivo.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Luo
authors.forename: Marguerite
authors.initials: M
authors.lastname: Prior
authors.forename: Wanxia
authors.initials: W
authors.lastname: He
authors.forename: Xiangyou
authors.initials: X
authors.lastname: Hu
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Tang
authors.forename: Weizhen
authors.initials: W
authors.lastname: Shen
authors.forename: Satya
authors.initials: S
authors.lastname: Yadav
authors.forename: Sumiko
authors.initials: S
authors.lastname: Kiryu-Seo
authors.forename: Robert
authors.initials: R
authors.lastname: Miller
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
authors.forename: Riqiang
authors.initials: R
authors.lastname: Yan
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C094131:NRG1 protein, human; D020890:Neuregulin-1; D020033:Protein Isoforms; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human