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

2016; Springer Nature; Volume: 23; Issue: 6 Linguagem: Inglês

10.1038/cdd.2015.163

1476-5403

Mauricio Gómez‐Suárez, Itzel Zenidel Gutiérrez-Martínez, José Antonio Hernández-Trejo, Marcela Hernández-Ruíz, Dimelza Suárez-Pérez, Aurora Candelario, Ryuta Kamekura, Óscar Medina‐Contreras, Michael Schnoor, Vianney Ortiz‐Navarrete, Nicolás Villegas‐Sepúlveda, Charles A. Parkos, Asma Nusrat, Porfirio Nava,

PI3K/AKT/mTOR signaling in cancer

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 IFNγ and TNFα treatment induce degradation of the PDK1 inhibitor, 14-3-3η, in intestinal epithelial cells. This mechanism requires association of 14-3-3ζ with raptor in a process that triggers autophagy and leads to 14-3-3η 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.