IFNγ-induced suppression of β-catenin signaling: evidence for roles of Akt and 14.3.3ζ

Author:

Nava Porfirio12,Kamekura Ryuta1,Quirós Miguel1,Medina-Contreras Oscar13,Hamilton Ross W.1,Kolegraff Keli N.1,Koch Stefan14,Candelario Aurora2,Romo-Parra Hector25,Laur Oskar1,Hilgarth Roland S.1,Denning Timothy L.13,Parkos Charles A.1,Nusrat Asma1

Affiliation:

1. Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322

2. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico

3. Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303

4. Division of Molecular Embryology, German Cancer Research Center, 69120 Heidelberg, Germany

5. Institute of Physiology I (Neurophysiology), Westfälische Wilhelms-University Münster, 48149 Münster, Germany

Abstract

The proinflammatory cytokine interferon γ (IFNγ ) influences intestinal epithelial cell (IEC) homeostasis in a biphasic manner by acutely stimulating proliferation that is followed by sustained inhibition of proliferation despite continued mucosal injury. β-Catenin activation has been classically associated with increased IEC proliferation. However, we observed that IFNγ inhibits IEC proliferation despite sustained activation of Akt/β-catenin signaling. Here we show that inhibition of Akt/β-catenin–mediated cell proliferation by IFNγ is associated with the formation of a protein complex containing phosphorylated β-catenin 552 (pβ-cat552) and 14.3.3ζ. Akt1 served as a bimodal switch that promotes or inhibits β-catenin transactivation in response to IFNγ stimulation. IFNγ initially promotes β-catenin transactivation through Akt-dependent C-terminal phosphorylation of β-catenin to promote its association with 14.3.3ζ. Augmented β-catenin transactivation leads to increased Akt1 protein levels, and active Akt1 accumulates in the nucleus, where it phosphorylates 14.3.3ζ to translocate 14.3.3ζ/β-catenin from the nucleus, thereby inhibiting β-catenin transactivation and IEC proliferation. These results outline a dual function of Akt1 that suppresses IEC proliferation during intestinal inflammation.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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