Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases

• Autores: Humphrey, Rohan K.; Yu, Shu-Mei; Flores, Luis Emilio; Jhala, Ulupi S.
• Año de publicación: 2010
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Glucose; Pdx1; AKT; GSK3
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

The pancreatic beta cell is sensitive to even small changes in PDX1 protein levels; consequently, Pdx1 haploinsufficiency can inhibit beta cell growth and decrease insulin biosynthesis and gene expression, leading to compromised glucose-stimulated insulin secretion. Using metabolic labeling of primary islets and a cultured β cell line, we show that glucose levels modulate PDX1protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose. Glucose-stimulated activation of AKT and inhibition of GSK3 decrease PDX1 phosphorylation and delay degradation. Furthermore, direct pharmacologic inhibition of AKT destabilizes, and inhibition of GSK3 increasesPDX1proteinstability.These studies define a novel functional role for the PDX1 C terminus in mediating the effects of glucose and demonstrate that glucose modulates PDX1 stability via the AKT-GSK3 axis.
Fil: Humphrey, Rohan K.. University of California at San Diego; Estados Unidos
Fil: Yu, Shu-Mei. University of California at San Diego; Estados Unidos
Fil: Flores, Luis Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Centro de Endocrinología Experimental y Aplicada (i); Argentina. University of California at San Diego; Estados Unidos
Fil: Jhala, Ulupi S.. University of California at San Diego; Estados Unidos. University Johns Hopkins; Estados Unidos