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IFN gamma-induced suppression of beta-catenin signaling: evidence for roles of Akt and 14.3.3 zeta
Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Mexico City, Mexico.
Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
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2014 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, no 19, p. 2894-2904Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Bethesda, United States: American Society for Cell Biology , 2014. Vol. 25, no 19, p. 2894-2904
Keywords [en]
14-3-3 Proteins/*metabolism, Animals, CHO Cells, Cell Line, Cell Proliferation, Cricetulus, Enzyme Activation, Inflammation, Interferon-gamma/metabolism/*pharmacology, Intestinal Mucosa/*cytology, Mice, Mice, Inbred C57BL, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*metabolism, Signal Transduction, beta Catenin/*antagonists & inhibitors
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-141665DOI: 10.1091/mbc.E13-09-0512ISI: 000343124100002PubMedID: 25079689Scopus ID: 2-s2.0-84929255585ISBN: 1939-4586 (Electronic) 1059-1524 (Linking) OAI: oai:DiVA.org:liu-141665DiVA, id: diva2:1149702
Note

Nava, Porfirio Kamekura, Ryuta Quiros, Miguel Medina-Contreras, Oscar Hamilton, Ross W Kolegraff, Keli N Koch, Stefan Candelario, Aurora Romo-Parra, Hector Laur, Oskar Hilgarth, Roland S Denning, Timothy L Parkos, Charles A Nusrat, Asma eng R01 DK079392/DK/NIDDK NIH HHS/ DK55679/DK/NIDDK NIH HHS/ R29 DK055679/DK/NIDDK NIH HHS/ R01 DK097256/DK/NIDDK NIH HHS/ DK72564/DK/NIDDK NIH HHS/ DK64399/DK/NIDDK NIH HHS/ R01 DK072564/DK/NIDDK NIH HHS/ DK53202/DK/NIDDK NIH HHS/ 1R01DK097256/DK/NIDDK NIH HHS/ R24 DK064399/DK/NIDDK NIH HHS/ DK59888/DK/NIDDK NIH HHS/ DK79392/DK/NIDDK NIH HHS/ R01 DK055679/DK/NIDDK NIH HHS/ R01 DK061379/DK/NIDDK NIH HHS/ R01 DK059888/DK/NIDDK NIH HHS/ DK61379/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2014/08/01 06:00 Mol Biol Cell. 2014 Oct 1;25(19):2894-904. doi: 10.1091/mbc.E13-09-0512. Epub 2014 Jul 30.

Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2018-03-06Bibliographically approved

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