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Updated: Sep 7, 2025

Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
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PI3Kγ is a novel regulator of TNFα signaling in the human colon cell line HT29/B6

Franz-Leonard Klaus1, Cornelia Kirsch1, Jörg P Müller2

  • 1Institute of Biochemistry II, Jena University Hospital, Jena, Germany.

Annals of the New York Academy of Sciences
|June 21, 2022
PubMed

Insights

Phosphoinositide 3-kinase gamma (PI3Kγ) deficiency protects against inflammatory bowel disease triggers. PI3Kγ acts independently of its kinase activity, suggesting a novel scaffolding role in maintaining epithelial barrier integrity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Phosphoinositide 3-kinases (PI3Ks) regulate essential cellular processes.
  • PI3K signaling is implicated in inflammatory bowel diseases (IBD) via tumor necrosis factor α (TNFα)-induced tight junction (TJ) disruption.
  • The specific roles of individual PI3K isoforms in epithelial barrier function remain unclear.

Purpose of the Study:

  • To investigate the role of PI3Kγ in TNFα-induced epithelial barrier dysfunction.
  • To determine if PI3Kγ's function is kinase-dependent or independent.

Main Methods:

  • Utilized wild-type and PI3Kγ-deficient HT-29/B6 cells.
  • Assessed epithelial barrier function using transepithelial electrical resistance (TEER) and paracellular flux assays.
  • Analyzed TJ protein distribution (ZO-1, claudin-2) via immunostaining.
  • Evaluated the effect of a pan-PI3K inhibitor.

Main Results:

  • PI3Kγ-deficient cells exhibited resistance to TNFα-induced barrier dysfunction compared to wild-type cells.
  • This protective effect was observed irrespective of PI3K activity, as shown by pan-PI3K inhibitor treatment.
  • Absence of PI3Kγ altered ZO-1 distribution and reduced basal claudin-2 levels.

Conclusions:

  • PI3Kγ plays a significant role in TNFα-induced epithelial barrier impairment.
  • PI3Kγ mediates this effect through a noncanonical, kinase-independent scaffolding mechanism.
  • Targeting PI3Kγ may offer a therapeutic strategy for inflammatory bowel diseases.
Keywords:
HT-29/B6 cellsPI3KγTERTNFαbarrier functionclaudintight junction

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