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Down-regulation of MEK/ERK signaling by E-cadherin-dependent PI3K/Akt pathway in differentiating intestinal

Patrick Laprise1, Marie-Josée Langlois, Marie-Josée Boucher

  • 1CIHR Group on Functional Development and Physiopathology of the Digestive Tract, Département d'Anatomie et Biologie Cellulaire, Faculté de Médecine, Université de Sherbrooke, Québec, Canada.

Journal of Cellular Physiology
|February 24, 2004
PubMed

Insights

E-cadherin-mediated cell-cell contacts in intestinal cells inhibit the ERK pathway via PI3K/Akt signaling, controlling proliferation and differentiation. This mechanism is crucial for intestinal epithelial development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Gastroenterology

Background:

  • Cell-cell contacts are vital for intestinal epithelial function, influencing cell cycle arrest and differentiation.
  • E-cadherin is a key mediator of cell-cell adhesion in epithelial tissues.
  • The ERK pathway plays a role in regulating cell proliferation and differentiation.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which E-cadherin-mediated cell-cell contacts regulate the ERK pathway in intestinal epithelial cells.
  • To investigate the role of the PI3K/Akt pathway in E-cadherin-induced ERK inhibition.

Main Methods:

  • Utilized Caco-2/15 intestinal epithelial cell cultures.
  • Performed calcium switch experiments to disrupt and restore cell-cell junctions.
  • Employed E-cadherin blocking antibodies, PI3K inhibitor (LY294002), and adenoviral infection with constitutively active Akt1.
  • Assessed Akt, MEK, and ERK phosphorylation levels via Western blotting.

Main Results:

  • Disruption of cell junctions by calcium removal increased MEK and ERK activity while decreasing Akt phosphorylation.
  • E-cadherin engagement, confirmed by blocking antibodies, led to Akt phosphorylation and MEK-ERK inhibition.
  • PI3K/Akt pathway activation was necessary for E-cadherin-mediated ERK inhibition.
  • Constitutively active Akt1 repressed ERK1/2 activity, and PI3K inhibition abolished Akt activity, leading to ERK activation in differentiating cells.

Conclusions:

  • E-cadherin engagement initiates MEK/ERK pathway inhibition through a PI3K/Akt-dependent mechanism.
  • This signaling pathway is critical for regulating the transition between proliferation and differentiation in intestinal epithelial cells.
  • The findings provide insight into the role of E-cadherin in intestinal crypt-villus axis development.

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