Ectodomain shedding-dependent transactivation of epidermal growth factor receptors in response to insulin-like growth factor type I

Mol Endocrinol. 2004 Nov;18(11):2727-39. doi: 10.1210/me.2004-0174. Epub 2004 Jul 22.


Diverse extracellular stimuli activate the ERK1/2 MAPK cascade by transactivating epidermal growth factor (EGF) receptors. Here, we have examined the role of EGF receptors in IGF-I-stimulated ERK1/2 activation in several cultured cell lines. In human embryonic kidney 293 cells, IGF-I triggered proteolysis of heparin binding (HB)-EGF, increased tyrosine autophosphorylation of EGF receptors, stimulated EGF receptor inhibitor (AG1478)-sensitive ERK1/2 phosphorylation, and promoted EGF receptor endocytosis. In a mixed culture system that employed IGF-I receptor null murine embryo fibroblasts (MEFs) (R(-) cells) to detect paracrine signals produced by MEFs expressing the human IGF-I receptor (R(+) cells), stimulation of R(+) cells provoked rapid activation of green fluorescent protein-tagged ERK2 in cocultured R(-) cells. The R(-) cell response was abolished by either the broad-spectrum matrix metalloprotease inhibitor batimastat or by AG1478, indicating that it resulted from the proteolytic generation of an EGF receptor ligand from adjacent R(+) cells. These data suggest that the paracrine production of EGF receptor ligands leading to EGF receptor transactivation is a general property of IGF-I receptor signaling. In contrast, the contribution of transactivated EGF receptors to IGF-I-stimulated downstream events, such as ERK1/2 activation, varies in a cell type-dependent manner.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Endocytosis / physiology
  • ErbB Receptors / analysis
  • ErbB Receptors / metabolism
  • ErbB Receptors / physiology*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Metalloendopeptidases / antagonists & inhibitors
  • Mice
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Paracrine Communication*
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Phosphorylation / drug effects
  • Quinazolines
  • Rats
  • Receptors, Somatomedin / drug effects
  • Tetradecanoylphorbol Acetate / pharmacology
  • Thiophenes / pharmacology
  • Tyrosine / metabolism
  • Tyrphostins / pharmacology


  • Quinazolines
  • Receptors, Somatomedin
  • Thiophenes
  • Tyrphostins
  • RTKI cpd
  • Tyrosine
  • Phenylalanine
  • Insulin-Like Growth Factor I
  • batimastat
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 3
  • Metalloendopeptidases
  • Tetradecanoylphorbol Acetate