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Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation.

Publication ,  Journal Article
Hawes, BE; van Biesen, T; Koch, WJ; Luttrell, LM; Lefkowitz, RJ
Published in: J Biol Chem
July 21, 1995

Receptors that couple to the heterotrimeric G proteins, Gi or Gq, can stimulate phosphoinositide (PI) hydrolysis and mitogen-activated protein kinase (MAPK) activation. PI hydrolysis produces inositol 1,4,5-trisphosphate and diacylglycerol, leading to activation of protein kinase C (PKC), which can stimulate increased MAPK activity. However, the relationship between PI hydrolysis and MAPK activation in Gi and Gq signaling has not been clearly defined and is the subject of this study. The effects of several signaling inhibitors are assessed including expression of a peptide derived from the carboxyl terminus of the beta adrenergic receptor kinase 1 (beta ARKct), which specifically blocks signaling mediated by the beta gamma subunits of G proteins (G beta gamma), expression of dominant negative mutants of p21ras (RasN17) and p74raf-1 (N delta Raf), protein-tyrosine kinase (PTK) inhibitors and cellular depletion of PKC. The Gi-coupled alpha 2A adrenergic receptor (AR) stimulates MAPK activation which is blocked by expression of beta ARKct, RasN17, or N delta Raf, or by PTK inhibitors, but unaffected by cellular depletion of PKC. In contrast, MAPK activation stimulated by the Gq-coupled alpha 1B AR or M1 muscarinic cholinergic receptor is unaffected by expression of beta ARKct or RasN17 expression or by PTK inhibitors, but is blocked by expression of N delta Raf or by PKC depletion. These data demonstrate that Gi- and Gq-coupled receptors stimulate MAPK activation via distinct signaling pathways. G beta gamma is responsible for mediating Gi-coupled receptor-stimulated MAPK activation through a mechanism utilizing p21ras and p74raf independent of PKC. In contrast, G alpha mediates Gq-coupled receptor-stimulated MAPK activation using a p21ras-independent mechanism employing PKC and p74raf. To define the role of G beta gamma in Gi-coupled receptor-mediated PI hydrolysis and MAPK activation, direct stimulation with G beta gamma was used. Expression of G beta gamma resulted in MAPK activation that was sensitive to inhibition by expression of beta ARKct, RasN17, or N delta Raf or by PTK inhibitors, but insensitive to PKC depletion. By comparison, G beta gamma-mediated PI hydrolysis was not affected by beta ARKct, RasN17, or N delta Raf expression or by PTK inhibitors. Together, these results demonstrate that G beta gamma mediates MAPK activation and PI hydrolysis via independent signaling pathways.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 21, 1995

Volume

270

Issue

29

Start / End Page

17148 / 17153

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins p21(ras)
  • Protein Kinase C
  • Phosphatidylinositols
  • GTP-Binding Proteins
  • Enzyme Activation
  • Cricetinae
  • Calcium-Calmodulin-Dependent Protein Kinases
  • CHO Cells
  • Biochemistry & Molecular Biology
  • Animals
 

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Hawes, B. E., van Biesen, T., Koch, W. J., Luttrell, L. M., & Lefkowitz, R. J. (1995). Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation. J Biol Chem, 270(29), 17148–17153. https://doi.org/10.1074/jbc.270.29.17148
Hawes, B. E., T. van Biesen, W. J. Koch, L. M. Luttrell, and R. J. Lefkowitz. “Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation.J Biol Chem 270, no. 29 (July 21, 1995): 17148–53. https://doi.org/10.1074/jbc.270.29.17148.
Hawes BE, van Biesen T, Koch WJ, Luttrell LM, Lefkowitz RJ. Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation. J Biol Chem. 1995 Jul 21;270(29):17148–53.
Hawes, B. E., et al. “Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation.J Biol Chem, vol. 270, no. 29, July 1995, pp. 17148–53. Pubmed, doi:10.1074/jbc.270.29.17148.
Hawes BE, van Biesen T, Koch WJ, Luttrell LM, Lefkowitz RJ. Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation. J Biol Chem. 1995 Jul 21;270(29):17148–17153.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 21, 1995

Volume

270

Issue

29

Start / End Page

17148 / 17153

Location

United States

Related Subject Headings

  • Proto-Oncogene Proteins p21(ras)
  • Protein Kinase C
  • Phosphatidylinositols
  • GTP-Binding Proteins
  • Enzyme Activation
  • Cricetinae
  • Calcium-Calmodulin-Dependent Protein Kinases
  • CHO Cells
  • Biochemistry & Molecular Biology
  • Animals