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PMID:17655843

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Citation

Buffin-Meyer, B, Crassous, PA, Delage, C, Denis, C, Schaak, S and Paris, H (2007) 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. 574:85-93

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.

Links

PubMed Online version:10.1016/j.ejphar.2007.07.014

Keywords

ADAM Proteins/physiology; Caco-2 Cells; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases/metabolism; 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; Receptor, Epidermal Growth Factor/physiology; Receptors, Adrenergic, alpha-2/physiology; Wound Healing/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ADA2A

involved_in

GO:0007186: G protein-coupled receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P00533)
  • positively_regulates:(GO:0035624)

Seeded From UniProt

complete

HUMAN:ADA2A

involved_in

GO:0001819: positive regulation of cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA2A

involved_in

GO:0035624: receptor transactivation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P00533)

Seeded From UniProt

complete

HUMAN:ADA2A

part_of

GO:0016323: basolateral plasma membrane

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADA2A

involved_in

GO:0030335: positive regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA2A

involved_in

GO:0090303: positive regulation of wound healing

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA2A

involved_in

GO:0045741: positive regulation of epidermal growth factor-activated receptor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA2A

involved_in

GO:0051044: positive regulation of membrane protein ectodomain proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA2A

involved_in

GO:0050892: intestinal absorption

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA17

involved_in

GO:0035624: receptor transactivation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P00533)

Seeded From UniProt

complete

HUMAN:ADA17

involved_in

GO:0045741: positive regulation of epidermal growth factor-activated receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HBEGF

involved_in

GO:0030335: positive regulation of cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HBEGF

involved_in

GO:0090303: positive regulation of wound healing

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HBEGF

involved_in

GO:0007173: epidermal growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HBEGF

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR_original

GO:0051897: positive regulation of protein kinase B signaling cascade

IMP: Inferred from Mutant Phenotype: :

P


HUMAN:EGFR_original

GO:0051897: positive regulation of protein kinase B signaling cascade

IMP: Inferred from Mutant Phenotype:

P


HUMAN:EGFR

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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