EGF receptor transactivation and PI3-kinase mediate stimulation of ERK by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role in wound healing

Eur J Pharmacol. 2007 Nov 28;574(2-3):85-93. doi: 10.1016/j.ejphar.2007.07.014. Epub 2007 Jul 13.


Intestinal cells express alpha(2A)-adrenoreceptors that stimulate sodium and peptide absorption and promote cell proliferation. Involved mechanisms are poorly understood and are not fully related to inhibition of cAMP production. Previous study using a clone of CaCo2 cells expressing the human alpha(2A)-adrenoreceptor (CaCo2-3B) showed that alpha(2)-adrenoreceptor agonists cause extracellular signal-regulated kinase (ERK) phosphorylation. Present work examines the signaling pathway triggering ERK activation and investigates the consequence of alpha(2A)-adrenoreceptor stimulation on cell migration. Treatment of CaCo2-3B with the alpha(2)-adrenoreceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline (UK14304) induces not only ERK, but also Akt phosphorylation. Both effects are strongly attenuated by inhibition or desensitization of epidermal growth factor (EGF) receptor, matrix metalloproteinase (MMP) blockade, heparin-binding-EGF neutralization or phosphatidylinositol 3-kinase (PI3-kinase) inhibitors. Conditioned medium from UK14304-treated CaCo2-3B stimulates ERK in parental CaCo2 by a mechanism sensitive to EGF receptor and PI3-kinase inhibitors. Exposure of CaCo2-3B to UK14304 accelerates the wound healing. This effect is abolished by heparin-binding-EGF neutralization but not by mitomycin C, indicating that it results probably from increased cell spreading and/or migration. In conclusion, alpha(2A)-adrenoreceptor activates ERK and Akt in intestinal cells by a common pathway which depends on PI3-kinase activation and results from EGF receptor transactivation, via an autocrine/paracrine pathway implying MMP activation and heparin-binding-EGF shedding. Therefore, alpha(2A)-adrenoreceptor could have a positive role in intestinal regeneration in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / physiology
  • ADAM17 Protein
  • Brimonidine Tartrate
  • Caco-2 Cells
  • Enzyme Activation
  • ErbB Receptors / physiology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins / physiology
  • Intestinal Mucosa / metabolism*
  • Matrix Metalloproteinases / physiology
  • Phosphatidylinositol 3-Kinases / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinoxalines / pharmacology
  • Receptors, Adrenergic, alpha-2 / physiology*
  • Wound Healing / physiology*


  • ADRA2A protein, human
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Quinoxalines
  • Receptors, Adrenergic, alpha-2
  • Brimonidine Tartrate
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • ADAM Proteins
  • Matrix Metalloproteinases
  • ADAM17 Protein