Heregulin-stimulated acetylcholine receptor gene expression in muscle: requirement for MAP kinase and evidence for a parallel inhibitory pathway independent of electrical activity

Binding of heregulin (HRG) to its receptor, ErbB3, results in a dimerization with ErbB2/neu and activation of their intrinsic tyrosine kinases, initiating a cascade of events resulting in the stimulation of acetylcholine receptor (AChR) genes in muscle. Here we have examined the signalling downstream of the HRG receptor. We show that phosphatidylinositol 3′‐kinase (PI3K) and SHC bind to the HRG‐activated ErbB3 in myotubes. Subsequently, p70S6 kinase (p70 S6k ), and MAP kinase ERK2 and thereby p90 rsk are activated. However, inhibition of PI3K and p70 S6k by wortmannin and rapamycin, respectively, failed to antagonize AChR α‐subunit gene expression stimulated by HRG, despite the fact that the activities of the kinases were inhibited. In contrast, these inhibitors elevated AChR α‐subunit mRNA levels, by themselves, independently of muscle electrical activity. On the other hand, the 17mer antisense oligonucleotide, EAS1, caused a specific depletion of ERK2 and eliminated the ability of HRG to stimulate AChR α‐subunit gene expression. These results indicate that HRG stimulates expression of AChR genes via ERK2 activation, and provide a physiological example of neurotrophic factor‐associated repression of AChR genes by stimulation of p70 S6k activity which may contribute to the expression of adult type AChR genes at the neuromuscular junction.