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In Vitro and In Vivo Approaches to Determine Intestinal Epithelial Cell Permeability
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Published on: October 19, 2018

Cyclic AMP-dependent protein kinase A negatively modulates adherens junction integrity and differentiation of

Marie-Josée Boucher1, Patrick Laprise, Nathalie Rivard

  • 1CIHR Group on Functional Development and Physiopathology of the Digestive Tract, Département d'Anatomie et Biologie Cellulaire, Faculty of Medicine, University of Sherbrooke, QC, Canada.

Journal of Cellular Physiology
|September 25, 2004
PubMed
Abstract

Insights

Cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) signaling negatively impact intestinal epithelial cell differentiation. This pathway disrupts cell junctions and hinders the development of enterocyte-like features, affecting cell polarity and brush border formation.

Area of Science:

  • Cell Biology
  • Gastroenterology
  • Molecular Biology

Background:

  • Intestinal epithelial cell differentiation is crucial for gut function.
  • The role of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) signaling in this process is not fully understood.
  • Previous studies suggest cAMP may inhibit enterocyte differentiation.

Purpose of the Study:

  • To elucidate the mechanisms by which cAMP/PKA signaling modulates human intestinal epithelial cell differentiation.
  • To investigate the impact of cAMP on key differentiation markers and cell junction integrity.

Main Methods:

  • Caco-2/15 cells were treated with 8Br-cAMP to mimic increased cAMP levels.
  • Effects on protein expression (sucrase-isomaltase, villin, E-cadherin, catenins, ZO-1) and cell morphology were assessed.
  • Immunofluorescence microscopy was used to analyze F-actin and protein localization at cell-cell contacts.
  • Protein kinase A (PKA) inhibition was achieved using H89.
  • Recruitment and activation of p85/PI-3K to E-cadherin complexes were examined.

Main Results:

  • 8Br-cAMP treatment repressed sucrase-isomaltase and villin expression, key markers of enterocyte differentiation.
  • Morphological differentiation, including cell polarity and brush border formation, was attenuated by 8Br-cAMP.
  • Adherens junction integrity was compromised, with reduced E-cadherin and catenins at cell interfaces and decreased association with the actin cytoskeleton.
  • PKA inhibition by H89 protected adherens junctions from disruption.
  • cAMP/PKA signaling prevented the recruitment of p85/PI-3K to E-cadherin, impacting adherens junction assembly.
  • E-cadherin phosphorylation on serine was observed in a PKA-dependent manner.

Conclusions:

  • cAMP/PKA signaling acts as a negative regulator of intestinal epithelial cell differentiation.
  • This pathway disrupts adherens junction integrity, affecting cell-cell adhesion and communication.
  • The findings provide insights into the molecular mechanisms underlying the inhibition of enterocyte differentiation by cAMP.

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