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 ty rosine kinases (RTKs), is likely to be one nerve-supplied signal that induces expression of acetylcholine receptor (AChR) genes at the devel oping neuromuscular junction. Since some RTKs act through Ras and phos phatidylinositol 3-kinase (PI3K), we investigated the role of these pa thways 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, expre ssion of an activated PI3K led to ARIA-independent AChR epsilon subuni t expression, and inhibition of PI3K abolished the action of ARIA. Thu s, synaptic induction of AChR genes requires activation of both Ras/MA PK and PI3K signal transduction pathways.