TY - JOUR
T1 - β2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf
AU - Schmitt, J. M.
AU - Stork, P. J.S.
PY - 2000/8/18
Y1 - 2000/8/18
N2 - 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 βγ 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 β2-adrenergic receptor (β2AR), to stimulate extracellular signal-regulated kinases (ERKs). Using HEK293 cells, which express endogenous β2AR, we show that isoproterenol stimulates ERKs via β2AR. This action of isoproterenol requires cAMP-dependent protein kinase and is insensitive to pertussis toxin, suggesting that Gα(s) activation of cAMP-dependent protein kinase is required. Interestingly, β2AR activates both the small G proteins Rap1 and Ras, but only Rap1 is capable of coupling to Raf isoforms. β2AR inhibits the Ras-dependent activation of both Raf isoforms Raf-1 and B-Raf, whereas Rap1 activation by isoproterenol recruits and activates B-Raf. β2AR 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 B-Raf in these cells.
AB - 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 βγ 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 β2-adrenergic receptor (β2AR), to stimulate extracellular signal-regulated kinases (ERKs). Using HEK293 cells, which express endogenous β2AR, we show that isoproterenol stimulates ERKs via β2AR. This action of isoproterenol requires cAMP-dependent protein kinase and is insensitive to pertussis toxin, suggesting that Gα(s) activation of cAMP-dependent protein kinase is required. Interestingly, β2AR activates both the small G proteins Rap1 and Ras, but only Rap1 is capable of coupling to Raf isoforms. β2AR inhibits the Ras-dependent activation of both Raf isoforms Raf-1 and B-Raf, whereas Rap1 activation by isoproterenol recruits and activates B-Raf. β2AR 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 B-Raf in these cells.
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U2 - 10.1074/jbc.M003213200
DO - 10.1074/jbc.M003213200
M3 - Article
C2 - 10840035
AN - SCOPUS:0034682836
SN - 0021-9258
VL - 275
SP - 25342
EP - 25350
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 33
ER -