Activation of p70/p85 S6 kinase by a pathway independent of p21ras

Nature. 1994 Sep 29;371(6496):426-9. doi: 10.1038/371426a0.


The enzymes p70s6k and p85s6k are two isoforms of the same kinase and are important in mitogenesis. Both isoforms are activated by a complex phosphorylation event and lie on a common signalling pathway, distinct from that of the p42mapk/p44mapk kinases. Activation of p42mapk/p44mapk is triggered by sequential activation of the GDP-GTP exchange factor Sos, the GTP-binding protein p21ras, and protein kinases p74raf and p47mek (refs 7-10). As p21ras transformed cells have increased S6 phosphorylation, we tested whether the p70s6k/p85s6k signalling pathway bifurcates between p21ras and p42mapk/p44mapk. We found that mutants of p74raf and p21ras blocked activation of epitope-tagged p44mapk but not epitope-tagged p70s6k. Moreover, in cells expressing human platelet-derived growth factor receptors lacking the kinase-insert domain, the growth factor activates p21ras but not p70s6k/p85s6k. The critical autophosphorylation site for p70s6k/p85s6k activation within this domain is a tyrosine at residue 751. Our results show that the p70s6k/p85s6k signalling pathway is independent of p21ras, that it bifurcates from the p21ras pathway at the receptor, and that it is initiated by autophosphorylation at a specific site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Enzyme Activation
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Mutation
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-raf*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • Swine


  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-raf
  • Ribosomal Protein S6 Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)