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The inflammatory cytokine IFNγ regulates intestinal epithelial homeostasis by controlling the spatiotemporal localization of Akt, 14.3.3ζ and β‐catenin.
Author(s) -
Nava Porfirio,
Kamekura Ryuta,
Hamilton Ross,
MedinaContreras Oscar,
Kolegraff Keli N.,
Denning Timothy L.,
Parkos Charles,
Nusrat Asma
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.256.9
Subject(s) - microbiology and biotechnology , protein kinase b , transactivation , adherens junction , proinflammatory cytokine , catenin , akt1 , phosphorylation , chemistry , signal transduction , cell growth , biology , transcription factor , cancer research , wnt signaling pathway , inflammation , cell , cadherin , immunology , biochemistry , gene
The proinflammatory cytokine IFNγ modulates intestinal epithelial (IEC) homeostasis through effects on IEC proliferation. Epithelial proliferative responses are, in turn, regulated by β‐catenin, an adherens junction‐associated protein that differentially controls cell‐cell adhesion and gene transcription. Chronic exposure to IFNγ results in protein kinase B (PKB/Akt)‐mediated β‐catenin signaling that initially promotes, and subsequently suppresses IEC proliferation. The mechanism(s) governing the suppression of β‐catenin signaling are poorly understood. Here we show that the β‐catenin dependent, antiproliferative activity of IFNγ requires synthesis, activation and subcellular compartmentalization of 14.3.3ζ scaffold protein and the Akt isoform Akt1. 14.3.3ζ associates with phosphorylated β‐ catenin (pβ‐cat552) in IECs exposed to IFNγ that in turn promotes β‐catenin dependent‐Akt1 expression. Akt1 upregulation and its accumulation in the nucleus results in translocation of 14.3.3ζ and pβ‐cat552 from the nucleus to the cytosol thereby suppressing β‐ catenin transactivation and IEC proliferation. These results provide a mechanism by which IFNγ decreases active β‐catenin in the nucleus to suppress IEC proliferation during inflammation.