Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors

Nature. 1996 Feb 8;379(6565):557-60. doi: 10.1038/379557a0.


Transduction of a mitogenic signal from the cell membrane to the nucleus involves the adapter proteins SHC and Grb2, which mediate activation of the Ras/mitogen-activated protein (MAP) kinase pathway. In contrast to receptor tyrosine kinases (RTKs), the signalling steps leading to Ras/MAP kinase activation by G-protein-coupled receptors (GPCRs) are still poorly characterized but appear to include beta gamma subunits of heterotrimeric G-proteins and as-yet unidentified tyrosine kinases. We report here that the epidermal growth factor receptor (EGFR) and the neu oncoprotein become rapidly tyrosine-phosphorylated upon stimulation of Rat-1 cells with the GPCR agonists endothelin-1, lysophosphatic acid and thrombin, suggesting that there is an intracellular mechanism for transactivation. Specific inhibition of EGFR function by either the selective tyrphostin AG1478 or a dominant-negative EGFR mutant suppressed MAP kinase activation and strongly inhibited induction of fos gene expression and DNA synthesis. Our results demonstrate a role for RTKs as downstream mediators in GPCR mitogenic signalling and suggest a ligand-independent mechanism of RTK activation through intracellular signal crosstalk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Division / physiology
  • Cell Line
  • Endothelin Receptor Antagonists
  • Endothelins / pharmacology
  • Enzyme Activation
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Lipopolysaccharides / pharmacology
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Peptides, Cyclic / pharmacology
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Proto-Oncogene Proteins c-fos / genetics
  • Rats
  • Receptor, ErbB-2 / drug effects
  • Receptor, ErbB-2 / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction*
  • Thrombin / pharmacology
  • Transcriptional Activation*
  • Tyrosine / metabolism


  • Endothelin Receptor Antagonists
  • Endothelins
  • Lipopolysaccharides
  • Peptides, Cyclic
  • Proto-Oncogene Proteins c-fos
  • Recombinant Proteins
  • Tyrosine
  • ErbB Receptors
  • Receptor, ErbB-2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Thrombin
  • GTP-Binding Proteins
  • cyclo(Trp-Asp-Pro-Val-Leu)