title: IFNγ-induced suppression of β-catenin signaling: evidence for roles of Akt and 14.3.3ζ.
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.
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico.
authors: Porfirio
authors: P
authors: Nava
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Ryuta
authors: R
authors: Kamekura
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Miguel
authors: M
authors: Quirós
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
authors: Oscar
authors: O
authors: Medina-Contreras
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Ross W
authors: RW
authors: Hamilton
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Keli N
authors: KN
authors: Kolegraff
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Division of Molecular Embryology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Koch
authors: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico.
authors: Aurora
authors: A
authors: Candelario
authors: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico Institute of Physiology I (Neurophysiology), Westfälische Wilhelms-University Münster, 48149 Münster, Germany.
authors: Hector
authors: H
authors: Romo-Parra
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Oskar
authors: O
authors: Laur
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.
authors: Roland S
authors: RS
authors: Hilgarth
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303.
authors: Timothy L
authors: TL
authors: Denning
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 anusrat@emory.edu cparkos@emory.edu.
authors: Charles A
authors: CA
authors: Parkos
authors: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 anusrat@emory.edu cparkos@emory.edu.
authors: Asma
authors: A
authors: Nusrat
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D049109:Cell Proliferation; D003412:Cricetulus; D004789:Enzyme Activation; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: D048948:14-3-3 Proteins; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; C000590975:Ywhaz protein, mouse; C514862:Akt1 protein, mouse