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Contrasting effects of ERK on tight junction integrity in differentiated and under-differentiated Caco-2 cell

Sudhir Aggarwal1, Takuya Suzuki, William L Taylor

  • 1Department of Physiology, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.

The Biochemical Journal
|October 22, 2010
PubMed

Insights

Extracellular-signal-regulated kinase (ERK) impacts epithelial tight junctions differently based on cell differentiation. In differentiated cells, ERK protects tight junctions, while in undifferentiated cells, it disrupts them, influencing protein interactions.

Area of Science:

  • Cell Biology
  • Epithelial Biology
  • Molecular Signaling

Background:

  • Tight junctions maintain epithelial barrier function.
  • Extracellular-signal-regulated kinase (ERK) activation has contrasting effects on tight junction integrity.
  • The role of cell differentiation in ERK-mediated tight junction regulation is unclear.

Purpose of the Study:

  • To investigate how cell differentiation state influences ERK-mediated regulation of tight junctions in Caco-2 cells.
  • To elucidate the mechanisms behind the opposing effects of ERK on tight junction integrity.

Main Methods:

  • Utilized Caco-2 cell monolayers at different differentiation states.
  • Employed epidermal growth factor (EGF) and hydrogen peroxide (H2O2) to modulate tight junctions.
  • Used MEK inhibitor (U0126), ERK1/2 knockdown, and MEK1 expression constructs.
  • Assessed tight junction integrity, protein localization, and interactions with occludin.

Main Results:

  • ERK activation potentiated tight junction disruption in undifferentiated cells but prevented it in differentiated cells.
  • ERK knockdown/inhibition yielded opposite effects on tight junction integrity in undifferentiated versus differentiated cells.
  • ERK's subcellular localization differed: intracellular in undifferentiated cells, perijunctional in differentiated cells.
  • ERK regulated the association of protein phosphatase 2A (PP2A) and protein kinase Cζ (PKCζ) with occludin in a differentiation-dependent manner.

Conclusions:

  • Cell differentiation state dictates ERK's influence on tight junction integrity.
  • Subcellular localization of ERK and its regulation of PKCζ and PP2A interactions with occludin underlie these contrasting effects.
  • Findings reveal a novel mechanism for differential regulation of epithelial barrier function by ERK signaling.

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