Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2

Michael Tanowitz, Jutong Si, De Hua Yu, Gen Sheng Feng, Lin Mei

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Synapse-specific expression of the nicotinic acetylcholine receptor (AChR) is believed to be mediated by neuregulin, an epidermal growth factor- like trophic factor released by somatic motoneurons at the neuromuscular junction (NMJ). Neuregulin stimulates ErbB2, ErbB3, and ErbB4, members of the ErbB family of receptor tyrosine kinases. SHP2 is a cytoplasmic protein tyrosine phosphatase containing two Src homology 2 domains near its N terminus, and has been shown to be a positive mediator of mitogenic responses to various growth factors. We found that SHP2 interacted with ErbB2 and ErbB3 after neuregulin stimulation of muscle cells. Expression of SHP2 in C2C12 mouse muscle cells attenuated the neuregulin-induced expression of an AChR ε-promoter reporter gene, whereas a catalytically inactive SHP2 mutant or a mutant lacking the N-terminal Src homology 2 (SH2) domain enhanced reporter expression, suggesting that SHP2 negatively regulates the neuregulin signaling pathway. In fibroblast cells that express a mutant SHP2 with a targeted deletion of the N-terminal SH2 domain, neuregulin-mediated activation of the Ras/Raf/extracellular signal-regulated kinase cascade was enhanced. Furthermore, we found that SHP2 immunoreactivity colocalized with the staining of α-bungarotoxin, a marker of the NMJ. These results demonstrate a negative role of SHP2 in the neuregulin signal that leads to AChR gene expression at the NMJ.

Original languageEnglish (US)
Pages (from-to)9426-9435
Number of pages10
JournalJournal of Neuroscience
Volume19
Issue number21
StatePublished - Nov 1 1999

Fingerprint

Neuregulins
Protein Tyrosine Phosphatases
Cholinergic Receptors
src Homology Domains
Neuromuscular Junction
Muscle Cells
Bungarotoxins
Extracellular Signal-Regulated MAP Kinases
Nicotinic Receptors
Motor Neurons
Reporter Genes
Epidermal Growth Factor
Protein-Tyrosine Kinases
Synapses
Intercellular Signaling Peptides and Proteins
Fibroblasts
Staining and Labeling
Gene Expression

Keywords

  • AChR
  • ErbB
  • Neuregulin
  • Neuromuscular junction
  • SHP2
  • Tyrosine phosphatase

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Tanowitz, M., Si, J., Yu, D. H., Feng, G. S., & Mei, L. (1999). Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2. Journal of Neuroscience, 19(21), 9426-9435.

Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2. / Tanowitz, Michael; Si, Jutong; Yu, De Hua; Feng, Gen Sheng; Mei, Lin.

In: Journal of Neuroscience, Vol. 19, No. 21, 01.11.1999, p. 9426-9435.

Research output: Contribution to journalArticle

Tanowitz, M, Si, J, Yu, DH, Feng, GS & Mei, L 1999, 'Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2', Journal of Neuroscience, vol. 19, no. 21, pp. 9426-9435.
Tanowitz, Michael ; Si, Jutong ; Yu, De Hua ; Feng, Gen Sheng ; Mei, Lin. / Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2. In: Journal of Neuroscience. 1999 ; Vol. 19, No. 21. pp. 9426-9435.
@article{e8c6b5d237c64fc0b9c25973869b9239,
title = "Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2",
abstract = "Synapse-specific expression of the nicotinic acetylcholine receptor (AChR) is believed to be mediated by neuregulin, an epidermal growth factor- like trophic factor released by somatic motoneurons at the neuromuscular junction (NMJ). Neuregulin stimulates ErbB2, ErbB3, and ErbB4, members of the ErbB family of receptor tyrosine kinases. SHP2 is a cytoplasmic protein tyrosine phosphatase containing two Src homology 2 domains near its N terminus, and has been shown to be a positive mediator of mitogenic responses to various growth factors. We found that SHP2 interacted with ErbB2 and ErbB3 after neuregulin stimulation of muscle cells. Expression of SHP2 in C2C12 mouse muscle cells attenuated the neuregulin-induced expression of an AChR ε-promoter reporter gene, whereas a catalytically inactive SHP2 mutant or a mutant lacking the N-terminal Src homology 2 (SH2) domain enhanced reporter expression, suggesting that SHP2 negatively regulates the neuregulin signaling pathway. In fibroblast cells that express a mutant SHP2 with a targeted deletion of the N-terminal SH2 domain, neuregulin-mediated activation of the Ras/Raf/extracellular signal-regulated kinase cascade was enhanced. Furthermore, we found that SHP2 immunoreactivity colocalized with the staining of α-bungarotoxin, a marker of the NMJ. These results demonstrate a negative role of SHP2 in the neuregulin signal that leads to AChR gene expression at the NMJ.",
keywords = "AChR, ErbB, Neuregulin, Neuromuscular junction, SHP2, Tyrosine phosphatase",
author = "Michael Tanowitz and Jutong Si and Yu, {De Hua} and Feng, {Gen Sheng} and Lin Mei",
year = "1999",
month = "11",
day = "1",
language = "English (US)",
volume = "19",
pages = "9426--9435",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "21",

}

TY - JOUR

T1 - Regulation of neuregulin-mediated acetylcholine receptor synthesis by protein tyrosine phosphatase SHP2

AU - Tanowitz, Michael

AU - Si, Jutong

AU - Yu, De Hua

AU - Feng, Gen Sheng

AU - Mei, Lin

PY - 1999/11/1

Y1 - 1999/11/1

N2 - Synapse-specific expression of the nicotinic acetylcholine receptor (AChR) is believed to be mediated by neuregulin, an epidermal growth factor- like trophic factor released by somatic motoneurons at the neuromuscular junction (NMJ). Neuregulin stimulates ErbB2, ErbB3, and ErbB4, members of the ErbB family of receptor tyrosine kinases. SHP2 is a cytoplasmic protein tyrosine phosphatase containing two Src homology 2 domains near its N terminus, and has been shown to be a positive mediator of mitogenic responses to various growth factors. We found that SHP2 interacted with ErbB2 and ErbB3 after neuregulin stimulation of muscle cells. Expression of SHP2 in C2C12 mouse muscle cells attenuated the neuregulin-induced expression of an AChR ε-promoter reporter gene, whereas a catalytically inactive SHP2 mutant or a mutant lacking the N-terminal Src homology 2 (SH2) domain enhanced reporter expression, suggesting that SHP2 negatively regulates the neuregulin signaling pathway. In fibroblast cells that express a mutant SHP2 with a targeted deletion of the N-terminal SH2 domain, neuregulin-mediated activation of the Ras/Raf/extracellular signal-regulated kinase cascade was enhanced. Furthermore, we found that SHP2 immunoreactivity colocalized with the staining of α-bungarotoxin, a marker of the NMJ. These results demonstrate a negative role of SHP2 in the neuregulin signal that leads to AChR gene expression at the NMJ.

AB - Synapse-specific expression of the nicotinic acetylcholine receptor (AChR) is believed to be mediated by neuregulin, an epidermal growth factor- like trophic factor released by somatic motoneurons at the neuromuscular junction (NMJ). Neuregulin stimulates ErbB2, ErbB3, and ErbB4, members of the ErbB family of receptor tyrosine kinases. SHP2 is a cytoplasmic protein tyrosine phosphatase containing two Src homology 2 domains near its N terminus, and has been shown to be a positive mediator of mitogenic responses to various growth factors. We found that SHP2 interacted with ErbB2 and ErbB3 after neuregulin stimulation of muscle cells. Expression of SHP2 in C2C12 mouse muscle cells attenuated the neuregulin-induced expression of an AChR ε-promoter reporter gene, whereas a catalytically inactive SHP2 mutant or a mutant lacking the N-terminal Src homology 2 (SH2) domain enhanced reporter expression, suggesting that SHP2 negatively regulates the neuregulin signaling pathway. In fibroblast cells that express a mutant SHP2 with a targeted deletion of the N-terminal SH2 domain, neuregulin-mediated activation of the Ras/Raf/extracellular signal-regulated kinase cascade was enhanced. Furthermore, we found that SHP2 immunoreactivity colocalized with the staining of α-bungarotoxin, a marker of the NMJ. These results demonstrate a negative role of SHP2 in the neuregulin signal that leads to AChR gene expression at the NMJ.

KW - AChR

KW - ErbB

KW - Neuregulin

KW - Neuromuscular junction

KW - SHP2

KW - Tyrosine phosphatase

UR - http://www.scopus.com/inward/record.url?scp=0033232527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033232527&partnerID=8YFLogxK

M3 - Article

VL - 19

SP - 9426

EP - 9435

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 21

ER -