title: 14-3-3 Proteins regulate Akt Thr308 phosphorylation in intestinal epithelial cells.
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.
authors: Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: M
authors: M
authors: Gómez-Suárez
authors: Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: I Z
authors: IZ
authors: Gutiérrez-Martínez
authors: Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: J A
authors: JA
authors: Hernández-Trejo
authors: Departamento de Biomedicina Molecular del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: M
authors: M
authors: Hernández-Ruiz
authors: Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, IPN. Plan de Ayala s/n, Col. Santo Tomás, México, DF, México.|PROINMED, FES Iztacala, UNAM, Avenida de los Barrios #1, Col. Los Reyes Iztacala, Tlalnepantla, Estado de México, México.
authors: D
authors: D
authors: Suárez-Pérez
authors: Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: A
authors: A
authors: Candelario
authors: Department of Pathology, University of Michigan, Ann Arbor, 48109 MI, USA.
authors: R
authors: R
authors: Kamekura
authors: Laboratorio de Inmunología y Proteómica, Hospital Infantil de México 'Federico Gómez', México, DF 06720, México.
authors: O
authors: O
authors: Medina-Contreras
authors: Departamento de Biomedicina Molecular del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: M
authors: M
authors: Schnoor
authors: Departamento de Biomedicina Molecular del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: V
authors: V
authors: Ortiz-Navarrete
authors: Departamento de Biomedicina Molecular del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: N
authors: N
authors: Villegas-Sepúlveda
authors: Department of Pathology, University of Michigan, Ann Arbor, 48109 MI, USA.
authors: C
authors: C
authors: Parkos
authors: Department of Pathology, University of Michigan, Ann Arbor, 48109 MI, USA.
authors: A
authors: A
authors: Nusrat
authors: Departamento de Fisiología, Biofísica y Neurociencias del CINVESTAV, IPN. Av. IPN 2508, Col. San Pedro Zacatenco, México, DF CP07360, México.
authors: P
authors: P
authors: Nava
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013912:Threonine / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; C557642:BV02 compound; D001549:Benzamides; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D011720:Pyrazoles; D013912:Threonine; D007371:Interferon-gamma; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt