Receptor-tyrosine-kinase- and G beta gamma-mediated MAP kinase activation by a common signalling pathway

Nature. 1995 Aug 31;376(6543):781-4. doi: 10.1038/376781a0.


Mitogen-activated protein (MAP) kinases mediate the phosphorylation and activation of nuclear transcription factors that regulate cell growth. MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrinsic tyrosine kinase activity, or G-protein-coupled receptors (GPCR). RTK-mediated mitogenic signalling involves a series of SH2- and SH3-dependent protein-protein interactions between tyrosine-phosphorylated receptor, Shc, Grb2 and Sos, resulting in Ras-dependent MAP kinase activation. The beta gamma subunits of heterotrimeric G proteins (G beta gamma) also mediate Ras-dependent MAP kinase activation by an as-yet unknown mechanism. Here we demonstrate that activation of MAP kinase by Gi-coupled receptors is preceded by the G beta gamma-mediated tyrosine phosphorylation of Shc, leading to an increased functional association between Shc, Grb2 and Sos. Moreover, disruption of the Shc-Grb2-Sos complex blocks G beta gamma-mediated MAP kinase activation, indicating that G beta gamma does not mediate MAP kinase activation by a direct interaction with Sos. These results indicate that G beta gamma-mediated MAP kinase activation is initiated by a tyrosine phosphorylation event and proceeds by a pathway common to both GPCRs and RTKs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Cell Line
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism
  • GRB2 Adaptor Protein
  • GTP-Binding Proteins / metabolism*
  • Membrane Proteins / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Recombinant Proteins / metabolism
  • Shc Signaling Adaptor Proteins
  • Signal Transduction*
  • Son of Sevenless Proteins
  • Tyrosine / metabolism


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • GRB2 Adaptor Protein
  • Membrane Proteins
  • Proteins
  • Recombinant Proteins
  • Shc Signaling Adaptor Proteins
  • Son of Sevenless Proteins
  • Tyrosine
  • Epidermal Growth Factor
  • Protein Kinases
  • Receptor Protein-Tyrosine Kinases
  • GTP-Binding Proteins