PI3K is required for insulin-stimulated but not EGF-stimulated ERK1/2 activation

Eur J Cell Biol. 2006 May;85(5):367-74. doi: 10.1016/j.ejcb.2005.11.005. Epub 2006 Jan 10.


The Ras/Raf/extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling pathway is known to cross-talk with other signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt pathway. However, the role of PI3K in ERK-1/2 activation induced by tyrosine kinase receptors was not fully understood. Here, we report that two structurally distinct PI3K inhibitors, wortmannin and LY294002, inhibited insulin-induced activation of ERK1/2 but had no effect on EGF-induced activation of ERK1/2 in hepatocellular carcinoma BEL-7402 and SMMC-7721 cells, breast cancer MCF-7 cells, and prostate cancer LNCaP cells. Although protein kinase C could act as a mediator between PI3K and ERK1/2, protein kinase C inhibitor chelerythrine chloride did not inhibit insulin-induced ERK1/2 activation. Both insulin- and EGF-induced ERK1/2 activation are strictly dependent on Ras activation, however, wortmannin only inhibited insulin-induced, but not EGF-induced Ras activation. These results indicate that PI3K plays different roles in the activation of Ras/ERK1/2 signaling by insulin and EGF, and that insulin-stimulated, but not EGF-stimulated, ERK1/2 and Akt signalings diverge at PI3K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / metabolism
  • Androstadienes / metabolism
  • Benzophenanthridines / metabolism
  • Cell Line, Tumor
  • Chromones / metabolism
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • Humans
  • Insulin / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Morpholines / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / metabolism
  • Signal Transduction / physiology*
  • Wortmannin
  • ras Proteins / metabolism


  • Alkaloids
  • Androstadienes
  • Benzophenanthridines
  • Chromones
  • Insulin
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Epidermal Growth Factor
  • chelerythrine
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • ras Proteins
  • Wortmannin