Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation.
In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-Y CHEMICAL GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-Y GENE-Y CHEMICAL GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-Y CHEMICAL GENE-N GENE-Y GENE-N GENE-Y GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
forskolin isoproterenol PP2 tyrosine EGFR ERK GPCR ERK mucin EGFR PD98059 gastric mucin beta-adrenergic GPCR Src kinase EGFR receptor tyrosine kinase GPCR gastric mucin epidermal growth factor receptor EGFR cAMP mucin EGFR kinase PI3K mucin G protein-coupled receptor adenylate cyclase gastric mucin tyrosine kinase Src forskolin Gastric mucin SRC kinase epidermal growth factor receptor beta-adrenergic G protein-coupled receptor tyrosine [(3)H]glucosamine PD153035 wortmannin cAMP adenylate