title: EGF receptor transactivation and PI3-kinase mediate stimulation of ERK by alpha(2A)-adrenoreceptor in intestinal epithelial cells: a role in wound healing.
abstract: 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.
authors.affiliation: INSERM, U858/I2MR, Department of Renal and Cardiac remodelling, team #5, 1 avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. benedicte.buffin-meyer@toulouse.inserm.fr
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Buffin-Meyer
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Crassous
authors.forename: Christine
authors.initials: C
authors.lastname: Delage
authors.forename: Colette
authors.initials: C
authors.lastname: Denis
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schaak
authors.forename: Hervé
authors.initials: H
authors.lastname: Paris
mesh_terms: D051722:ADAM Proteins / Q000502:physiology; D000072198:ADAM17 Protein; D000068438:Brimonidine Tartrate; D018938:Caco-2 Cells; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: C547768:ADRA2A protein, human; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein