TY - JOUR
T1 - Neuregulin-increased expression of acetylcholine receptor ε-subunit gene requires ErbB interaction with Shc
AU - Won, Sandra
AU - Si, Jutong
AU - Colledge, Marcie
AU - Ravichandran, Kodimangalam S.
AU - Froehner, Stanley C.
AU - Mei, Lin
PY - 1999
Y1 - 1999
N2 - Selective transcription of acetylcholine receptor (AChR) subunit genes by neuregulin is one of the mechanisms involved in the synaptic localization of AChRs to the neuromuscular junction. Neuregulin stimulates ErbB receptor tyrosine kinases and subsequently activates the Ras/ERK pathway, which is required for neuregulin-mediated induction of AChR subunit genes in muscle cells and synapse-specific expression in vivo. Here we investigated the neuregulin transduction mechanism that leads to ERK activation after ErbB receptor tyrosine phosphorylation. Neuregulin increases the association of the adaptor proteins Grb2 and Shc with both ErbB2 and ErbB3 in C2C12 muscle cells. Dephosphorylation of the tyrosine-phosphorylated ErbB proteins abolished their association with both Grb2 and Shc, suggesting a tyrosine phosphorylation-dependent interaction. The interaction of Shc with the ErbB receptors is mediated by Shc's phosphotyrosine-binding domain. In addition, neuregulin increased tyrosine phosphorylation of Shc. Mutagenesis approaches demonstrated that tyrosine phosphorylation of Shc is required for neuregulin induction of AChR subunit gene expression. Taken together, these data indicate that the interaction of ErbB receptors with Grb2 alone is insufficient for neuregulin-activated transcription, but that ErbB receptor signaling via Shc is necessary and important.
AB - Selective transcription of acetylcholine receptor (AChR) subunit genes by neuregulin is one of the mechanisms involved in the synaptic localization of AChRs to the neuromuscular junction. Neuregulin stimulates ErbB receptor tyrosine kinases and subsequently activates the Ras/ERK pathway, which is required for neuregulin-mediated induction of AChR subunit genes in muscle cells and synapse-specific expression in vivo. Here we investigated the neuregulin transduction mechanism that leads to ERK activation after ErbB receptor tyrosine phosphorylation. Neuregulin increases the association of the adaptor proteins Grb2 and Shc with both ErbB2 and ErbB3 in C2C12 muscle cells. Dephosphorylation of the tyrosine-phosphorylated ErbB proteins abolished their association with both Grb2 and Shc, suggesting a tyrosine phosphorylation-dependent interaction. The interaction of Shc with the ErbB receptors is mediated by Shc's phosphotyrosine-binding domain. In addition, neuregulin increased tyrosine phosphorylation of Shc. Mutagenesis approaches demonstrated that tyrosine phosphorylation of Shc is required for neuregulin induction of AChR subunit gene expression. Taken together, these data indicate that the interaction of ErbB receptors with Grb2 alone is insufficient for neuregulin-activated transcription, but that ErbB receptor signaling via Shc is necessary and important.
KW - Acetylcholine receptor
KW - ErbB
KW - Grb2
KW - Neuregulin
KW - Neuromuscular junction
KW - Shc
KW - Tyrosine phosphorylation
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U2 - 10.1046/j.1471-4159.1999.0732358.x
DO - 10.1046/j.1471-4159.1999.0732358.x
M3 - Article
C2 - 10582594
AN - SCOPUS:0032705689
SN - 0022-3042
VL - 73
SP - 2358
EP - 2368
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 6
ER -