2. Academic Validation
  3. 14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells

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

  • Cell Death Differ. 2016 Jun;23(6):1060-72. doi: 10.1038/cdd.2015.163.
M Gómez-Suárez 1,  I Z Gutiérrez-Martínez 1,  J A Hernández-Trejo 1,  M Hernández-Ruiz 2,  D Suárez-Pérez 3 4,  A Candelario 1,  R Kamekura 5,  O Medina-Contreras 6,  M Schnoor 2,  V Ortiz-Navarrete 2,  N Villegas-Sepúlveda 2,  C Parkos 5,  A Nusrat 5,  P Nava 1
Affiliations

Affiliations

  • 1 Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
  • 2 Departamento de Biomedicina Molecular del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
  • 3 Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, IPN. Plan de Ayala s/n, Col. Santo Tomás, México, DF, México.
  • 4 PROINMED, FES Iztacala, UNAM, Avenida de los Barrios #1, Col. Los Reyes Iztacala, Tlalnepantla, Estado de México, México.
  • 5 Department of Pathology, University of Michigan, Ann Arbor, 48109 MI, USA.
  • 6 Laboratorio de Inmunología y Proteómica, Hospital Infantil de México 'Federico Gómez', México, DF 06720, México.
PMID: 26846144 DOI: 10.1038/cdd.2015.163
Abstract

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.

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