Induction of autocrine epidermal growth factor receptor ligands in human keratinocytes by insulin/insulin-like growth factor-1

J Cell Physiol. 1995 May;163(2):257-65. doi: 10.1002/jcp.1041630206.


Autocrine activation of the epidermal growth factor (EGF) receptor on keratinocytes has been recognized as an important growth regulatory mechanism involved in epithelial homeostasis, and, possibly, hyperproliferative diseases. Insulin-like growth factor (IGF)-1 and insulin have been shown to be paracrine keratinocyte mitogens that bind to the type I IGF receptor which is expressed on actively proliferating keratinocytes in situ. In this report, we demonstrate that IGF-1/insulin induced production of keratinocyte-derived autocrine growth factors that bind to the EGF receptor. Increased steady-state mRNA levels for transforming growth factor alpha (TGF-alpha) and for amphiregulin (AR) were observed upon incubation of keratinocytes with mitogenic concentrations of IGF-1. IGF-1 also induced production and secretion of TGF-alpha and AR proteins as detected by immunoassays. An EGF receptor antagonistic monoclonal antibody abolished the mitogenic effect of IGF-1 on cultured keratinocytes. These results suggest that stimulation of keratinocyte growth of IGF-1 requires activation of an EGF receptor-mediated autocrine loop.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin
  • Antibodies / immunology
  • Cell Division / drug effects
  • EGF Family of Proteins
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism*
  • Glycoproteins / metabolism
  • Growth Substances / metabolism
  • Humans
  • Insulin / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology*
  • Intercellular Signaling Peptides and Proteins*
  • Keratinocytes / metabolism*
  • Ligands
  • Transforming Growth Factor alpha / metabolism


  • AREG protein, human
  • Amphiregulin
  • Antibodies
  • EGF Family of Proteins
  • Glycoproteins
  • Growth Substances
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Transforming Growth Factor alpha
  • Insulin-Like Growth Factor I
  • ErbB Receptors