G protein-coupled receptors can induce cellular proliferation by stimulating the mitogen-activated protein (MAP) kinase cascade. Heterotrimeric G proteins are composed of both a and By subunits that can signal independently to diverse intracellular signaling pathways including those that activate MAP kinases. In this study, we examined the ability of isoproterenol, an agonist of the B2-adrenergic receptor (b2AR), to stimulate extracellular signal-regulated kinases (ERKs). Using HEK293 cells, which express endogenous b2AR, we show that isoproterenol stimulates ERKs via b2AR. This action of isoproterenol requires cAMP-dependent protein kinase and is insensitive to pertussis toxin, suggesting that Gas activation of cAMP-dependent protein kinase is required. Interestingly, b2AR activates both the small G proteins Rap1 and Ras, but only Rap1 is capable of coupling to Raf isoforms. b2AR inhibits the Ras-dependent activation of both Raf isoforms Raf-1 and B-Raf, whereas Rap1 activation by isoproterenol recruits and activates B-Raf. b2AR activation of ERKs is not blocked by expression of RasN17, an interfering mutant of Ras, but is blocked by expression of either RapN17 or Rap1GAP1, both of which interfere with Rap1 signaling. We propose that isoproterenol can activate ERKs via Rap1 and BRaf in these cells.
Schmitt, John M. and Stork, Philip J. S., "B2-Adrenergic Receptor Activates Extracellular Signal-regulated Kinases (ERKs) via the Small G Protein Rap1 and the Serine/Threonine Kinase B-Raf" (2000). Faculty Publications - Department of Biology and Chemistry. 50.