Tyrosine kinase-independent activation of extracellular-regulated kinase (ERK) 1/2 by the insulin-like growth factor-1 receptor

Cell Signal. 2011 Apr;23(4):739-46. doi: 10.1016/j.cellsig.2010.12.008. Epub 2011 Jan 6.


The extracellular-regulated kinase (ERK1/2) is a key conduit for transduction of signals from growth factor receptors to the nucleus. Previous work has shown that ERK1/2 activation in response to IGF-1 may require the participation of G proteins, but the role of the receptor tyrosine kinase in this process has not been clearly resolved. This investigation of IGF-1 receptor function was therefore designed to examine the contribution of the receptor tyrosine kinase to ERK1/2 activation. Phosphorylation of ERK1/2 in smooth muscle cells following treatment with IGF-1 was not blocked by pretreatment with AG1024 or picropodophylin, inhibitors of the IGF-1 receptor tyrosine kinase. Likewise, IGF-1 activated ERK1/2 in cells expressing a kinase-dead mutant of the IGF-1 receptor. ERK1/2 activation was unaffected by the phosphatidylinositol 3-kinase inhibitor LY-294002, but was sensitive to inhibitors of Src kinase, phospholipase C and Gβγ subunit signalling. Treatment with αIR-3, a neutralizing monoclonal antibody, also stimulated ERK1/2 phosphorylation without concomitant activation of the receptor tyrosine kinase. Phosphoprotein mapping of IGF-1 and αIR-3 treated cells confirmed that antibody-induced ERK1/2 phosphorylation occurred in the absence of tyrosine kinase phosphorylation, and enabled extension of these findings to p38 MAPK. These results suggest that stimulation of ERK1/2 phosphorylation by IGF-1 does not require activation of the receptor tyrosine kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Cell Culture Techniques
  • Coronary Vessels / cytology
  • Coronary Vessels / metabolism
  • Enzyme Activation
  • ErbB Receptors / antagonists & inhibitors
  • GTP-Binding Protein beta Subunits / antagonists & inhibitors
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / antagonists & inhibitors
  • GTP-Binding Protein gamma Subunits / metabolism
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Myocytes, Smooth Muscle / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology*
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors
  • Swine
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antibodies, Neutralizing
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Insulin-Like Growth Factor I
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Receptor, IGF Type 1
  • Receptors, Platelet-Derived Growth Factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases