IFN gamma-induced suppression of beta-catenin signaling: evidence for roles of Akt and 14.3.3 zeta

• Authors: Porfirio Nava, Emory University; Ryuta Kamekura, Emory University; Miguel Quirós, Emory University; Oskar Laur, Emory University; Oscar Medina-Contreras, Emory University; Ross W. Hamilton, Emory University; Keli N. Kolegraff, Emory University; Stefan Koch, Emory University; Aurora Candelario, Instituto Politécnico Nacional; Hector Romo-Parra, Instituto Politécnico Nacional; Oskar Laur, Emory University; Roland Hilgarth, Emory University; Timothy Denning, Emory University; Charles Parkos, Emory University; Asma Nusrat, Emory University
• Journal Title: Molecular Biology of the Cell
• Volume: Volume 25, Number 19
• Publisher: American Society for Cell Biology | 2014-10-01, Pages 2894-2904
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1091/mbc.E13-09-0512
• Subjects: Health Sciences, Pathology; Health Sciences, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; HUMAN KERATINOCYTE DIFFERENTIATION; 14-3-3 PROTEIN; PHOSPHATIDYLINOSITOL 3-KINASE; NEGATIVE REGULATOR; PROXIMITY LIGATION; CELL-PROLIFERATION; STEM-CELLS; IN-SITU; ACTIVATION; PATHWAY

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.