ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway.
AChR-inducing activity (ARIA)/heregulin, a ligand for erbB receptor tyrosine kinases (RTKs), is likely to be one nerve-supplied signal that induces expression of acetylcholine receptor (AChR) genes at the developing neuromuscular junction. Since some RTKs act through Ras and phosphatidylinositol 3-kinase (PI3K), we investigated the role of these pathways in ARIA signaling. Expression of activated Ras or Raf mimicked ARIA-induction of AChR epsilon subunit genes in muscle cells; whereas dominant negative Ras or Raf blocked the effect of ARIA. ARIA rapidly activated erk1 and erk2 and inhibition of both erks also abolished the effect of ARIA. ARIA stimulated association of PI3K with erbB3, expression of an activated PI3K led to ARIA-independent AChR epsilon subunit expression, and inhibition of PI3K abolished the action of ARIA. Thus, synaptic induction of AChR genes requires activation of both Ras/MAPK and PI3K signal transduction pathways.
Tansey
M G
MG
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St.Louis, Missouri 63110-8103, USA.
Chu
G C
GC
Merlie
J P
JP
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020890:Neuregulin-1; D009469:Neuromuscular Junction / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; D011978:Receptors, Nicotinic; D018631:ras Proteins; C094131:NRG1 protein, human