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Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by

Geetha Samak1, Kamaljit K Chaudhry1, Ruchika Gangwar1

  • 1*Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, U.S.A.

The Biochemical Journal
|November 8, 2014
PubMed

Insights

Dextran sodium sulfate (DSS) disrupts intestinal barrier function by activating a signaling cascade involving calcium, Ask1, MKK7, JNK2, and c-Src, leading to tight junction disruption in ulcerative colitis models.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Molecular Biology

Background:

  • Intestinal epithelial tight junction disruption is key in ulcerative colitis pathogenesis.
  • Dextran sodium sulfate (DSS) is a model inducer of colitis, but its mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism of DSS-induced tight junction disruption and barrier dysfunction.
  • To investigate the role of specific signaling pathways in DSS-induced colitis.

Main Methods:

  • Utilized Caco-2 cell monolayers in vitro and mouse colon in vivo models.
  • Assessed tight junction integrity, barrier function, and protein phosphorylation.
  • Employed JNK inhibitors, calcium chelators, and gene knockdown techniques (Ask1, MKK7, c-Src).

Main Results:

  • DSS disrupted tight junctions, adherens junctions, and the actin cytoskeleton, impairing barrier function.
  • DSS rapidly activated c-Jun N-terminal kinase (JNK2), apoptosis signal-regulated kinase 1 (Ask1), MKK7, and c-Src.
  • Increased intracellular calcium mediated DSS-induced JNK activation and tight junction disruption.
  • Inhibition of JNK, Ask1, MKK7, or c-Src attenuated DSS-induced barrier dysfunction.
  • DSS increased tyrosine phosphorylation of key junctional proteins like occludin and ZO-1.

Conclusions:

  • A Ca(2+)/Ask1/MKK7/JNK2/cSrc signaling cascade mediates DSS-induced tight junction disruption and barrier dysfunction.
  • This pathway is crucial for understanding ulcerative colitis pathogenesis and developing therapeutic strategies.

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