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Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras.

Publication ,  Journal Article
Koch, WJ; Hawes, BE; Allen, LF; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
December 20, 1994

Stimulation of Gi-coupled receptors leads to the activation of mitogen-activated protein kinases (MAP kinases). In several cell types, this appears to be dependent on the activation of p21ras (Ras). Which G-protein subunit(s) (G alpha or the G beta gamma complex) primarily is responsible for triggering this signaling pathway, however, is unclear. We have demonstrated previously that the carboxyl terminus of the beta-adrenergic receptor kinase, containing its G beta gamma-binding domain, is a cellular G beta gamma antagonist capable of specifically distinguishing G alpha- and G beta gamma-mediated processes. Using this G beta gamma inhibitor, we studied Ras and MAP kinase activation through endogenous Gi-coupled receptors in Rat-1 fibroblasts and through receptors expressed by transiently transfected COS-7 cells. We report here that both Ras and MAP kinase activation in response to lysophosphatidic acid is markedly attenuated in Rat-1 cells stably transfected with a plasmid encoding this G beta gamma antagonist. Likewise in COS-7 cells transfected with plasmids encoding Gi-coupled receptors (alpha 2-adrenergic and M2 muscarinic), the activation of Ras and MAP kinase was significantly reduced in the presence of the coexpressed G beta gamma antagonist. Ras-MAP kinase activation mediated through a Gq-coupled receptor (alpha 1-adrenergic) or the tyrosine kinase epidermal growth factor receptor was unaltered by this G beta gamma antagonist. These results identify G beta gamma as the primary mediator of Ras activation and subsequent signaling via MAP kinase in response to stimulation of Gi-coupled receptors.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

December 20, 1994

Volume

91

Issue

26

Start / End Page

12706 / 12710

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Receptors, Lysophosphatidic Acid
  • Receptors, G-Protein-Coupled
  • Receptors, Cell Surface
  • Receptors, Adrenergic, beta
  • Rats
  • Proto-Oncogene Proteins p21(ras)
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
 

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Koch, W. J., Hawes, B. E., Allen, L. F., & Lefkowitz, R. J. (1994). Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. Proc Natl Acad Sci U S A, 91(26), 12706–12710. https://doi.org/10.1073/pnas.91.26.12706
Koch, W. J., B. E. Hawes, L. F. Allen, and R. J. Lefkowitz. “Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras.Proc Natl Acad Sci U S A 91, no. 26 (December 20, 1994): 12706–10. https://doi.org/10.1073/pnas.91.26.12706.
Koch WJ, Hawes BE, Allen LF, Lefkowitz RJ. Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12706–10.
Koch, W. J., et al. “Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras.Proc Natl Acad Sci U S A, vol. 91, no. 26, Dec. 1994, pp. 12706–10. Pubmed, doi:10.1073/pnas.91.26.12706.
Koch WJ, Hawes BE, Allen LF, Lefkowitz RJ. Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12706–12710.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

December 20, 1994

Volume

91

Issue

26

Start / End Page

12706 / 12710

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Signal Transduction
  • Receptors, Lysophosphatidic Acid
  • Receptors, G-Protein-Coupled
  • Receptors, Cell Surface
  • Receptors, Adrenergic, beta
  • Rats
  • Proto-Oncogene Proteins p21(ras)
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases