14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

• Published in: Cell death and differentiation Vol. 23; no. 6; pp. 1060 - 1072
• Main Authors: Gómez-Suárez, M, Gutiérrez-Martínez, I Z, Hernández-Trejo, J A, Hernández-Ruiz, M, Suárez-Pérez, D, Candelario, A, Kamekura, R, Medina-Contreras, O, Schnoor, M, Ortiz-Navarrete, V, Villegas-Sepúlveda, N, Parkos, C, Nusrat, A, Nava, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2016; Nature Publishing Group
• Subjects: 13/106; 13/51; 14-3-3 Proteins - antagonists & inhibitors; 14-3-3 Proteins - metabolism; 14/1; 14/19; 3-Phosphoinositide-Dependent Protein Kinases - antagonists & inhibitors; 3-Phosphoinositide-Dependent Protein Kinases - metabolism; 631/250/127/1212; 631/250/1933; 82; 82/1; 82/29; 82/51; Animals; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; Benzamides - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Cell growth; Cell Line; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Epithelial Cells - cytology; Epithelial Cells - metabolism; Homeostasis; Inflammation; Inflammatory bowel disease; Interferon-gamma - pharmacology; Intestinal Mucosa - cytology; Kinases; Life Sciences; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Original Paper; Phosphorylation; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Subunits - antagonists & inhibitors; Protein Subunits - metabolism; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Pyrazoles - pharmacology; Signal Transduction - drug effects; Stem Cells; Threonine - metabolism; Tumor necrosis factor-TNF
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2015.163

Akt activation has been associated with proliferation, differentiation, survival and death of epithelial cells. Phosphorylation of Thr308 of Akt by phosphoinositide-dependent kinase 1 (PDK1) is critical for optimal stimulation of its kinase activity. However, the mechanism(s) regulating this process remain elusive. Here, we report that 14-3-3 proteins control Akt Thr308 phosphorylation during intestinal inflammation. Mechanistically, we found that IFN γ and TNF α treatment induce degradation of the PDK1 inhibitor, 14-3-3 η , in intestinal epithelial cells. This mechanism requires association of 14-3-3 ζ with raptor in a process that triggers autophagy and leads to 14-3-3 η degradation. Notably, inhibition of 14-3-3 function by the chemical inhibitor BV02 induces uncontrolled Akt activation, nuclear Akt accumulation and ultimately intestinal epithelial cell death. Our results suggest that 14-3-3 proteins control Akt activation and regulate its biological functions, thereby providing a new mechanistic link between cell survival and apoptosis of intestinal epithelial cells during inflammation.