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

• Type of Material: Article
• 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; Roland Hilgarth, Emory University; Timothy Denning, Emory University; Charles Parkos, Emory University; Asma Nusrat, Emory University
• Language: English
• Date: 2014-10-01
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Nava, Kamekura, Quirós, et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E13-09-0512
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 25
• Issue: 19
• Start Page: 2894
• End Page: 2904
• Grant/Funding Information: This work is supported by grants from the National Institutes of Health (1R01DK097256 to T.L.D.; DK72564, DK61379, and DK79392 to C.A.P.; DK53202, DK55679, and DK59888 to A.N.; and DK64399, a National Institutes of Health Digestive Diseases Research Development Center tissue culture and morphology grant), the American Gastroenterological Association (Research Scholar Award to P.N.), the Crohn's and Colitis Foundation of America (Senior Research Award to T.L.D.; Career Development Award to P.N.; and Fellowship Award to S.K. and O.M.C.), a grant from the Consejo Nacional de Ciencia y Tecnología (175854 to P.N.D.), and the Glaxo-SmithKline International Award from the Japan Society of Immunology and Allergology in Otolaryngology (to R.K.).
• Keywords: PROXIMITY LIGATION; ACTIVATION; Science & Technology; PHOSPHATIDYLINOSITOL 3-KINASE; CELL-PROLIFERATION; 14-3-3 PROTEIN; STEM-CELLS; Life Sciences & Biomedicine; PATHWAY; Cell Biology; IN-SITU; HUMAN KERATINOCYTE DIFFERENTIATION; NEGATIVE REGULATOR
• Research Categories: Health Sciences, Pathology; Health Sciences, General

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.