β2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf

J. M. Schmitt, P. J.S. Stork

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)25342-25350
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number33
DOIs
StatePublished - Aug 18 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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