beta(2)-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf

G protein-coupled receptors can induce cellular proliferation by stimulatin g the mitogen-activated protein (MAP) kinase cascade. Heterotrimeric G prot eins are composed of both alpha and beta gamma subunits that can signal ind ependently to diverse intracellular signaling pathways including those that activate MAP kinases. In this study, we examined the ability of isoprotere nol, an agonist of the beta(2)-adrenergic receptor (beta(2)AR), to stimulat e extracellular signal-regulated kinases (ERKs). Using HEK293 cells, which express endogenous beta(2)AR, we show that isoproterenol stimulates ERKs vi a beta(2)AR. This action of isoproterenol requires cAMP-dependent protein k inase and is insensitive to pertussis toxin, suggesting that G alpha(s) act ivation of cAMP-dependent protein kinase is required. Interestingly, beta(2 )AR activates both the small G proteins Rap1 and Res, but only Rap1 is capa ble of coupling to Raf isoforms. beta(2)AR inhibits the Ras-dependent activ ation of both Raf isoforms Raf-1 and B-Raf, whereas Rap1 activation by isop roterenol recruits and activates B-Raf. beta(2)AR activation of ERKs is not blocked by expression of RasN17, an interfering mutant of Ras, but is bloc ked by expression of either RapN17 or Rap1GAP1, both of which interfere wit h Rap1 signaling. We propose that isoproterenol can activate ERKs via Rap1 and B-Raf in these cells.