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 (p70S6k), and MAP kinase ERK2 and thereby p90rsk are activated. However, inhibition of PI3K and p70S6k by wortmannin and rapamycin, respectively, failed to antagonize AChR alpha-subunit gene expression stimulated by HRG, despite the fact that the activities of the kinases were inhibited. In contrast, these inhibitors elevated AChR alpha-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 alpha-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 p70S6k activity which may contribute to the expression of adult type AChR genes at the neuromuscular junction.
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CNRS UA D1284 Neurobiologie Moléculaire, Institut Pasteur, Paris, France.
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D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006023:Glycoproteins / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D009132:Muscles / Q000196:embryology; D020890:Neuregulin-1; D019319:Okadaic Acid / Q000494:pharmacology; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020893:Receptor, ErbB-3; D011950:Receptors, Cholinergic / Q000235:genetics*; D019893:Ribosomal Protein S6 Kinases; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin / Q000494:pharmacology; D000077191:Wortmannin
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000730:Androstadienes; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D006023:Glycoproteins; D006133:Growth Substances; D020890:Neuregulin-1; D019319:Okadaic Acid; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020893:Receptor, ErbB-3; D011950:Receptors, Cholinergic; D019893:Ribosomal Protein S6 Kinases; D055765:Shc Signaling Adaptor Proteins; D020123:Sirolimus; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D000077191:Wortmannin