Phosphorylation and Inactivation of GSK3{beta} by Dual-Specificity Tyrosine(Y)-Phosphorylation-Regulated Kinase 1A (Dyrk1A) [Signal Transduction]

December 4th, 2014 by Song, W.-J., Song, E.-A. C., Jung, M.-S., Choi, S.-H., Baik, H.-H., Jin, B. K., Kim, J. H., Chung, S.-H.

Glycogen synthase kinase 3β (GSK3β) participates in many cellular processes and its dysregulation has been implicated in a wide range of diseases such as obesity, type 2 diabetes, cancer, and Alzheimer's disease. Inactivation of GSK3β by phosphorylation at specific residues is a primary mechanism by which this constitutively active kinase is controlled; however, the regulatory mechanism of GSK3β is not fully understood. Dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) has multiple biological functions that occur as the result of phosphorylation of diverse proteins that are involved in metabolism, synaptic function, and neurodegeneration. Here, we show that GSK3β directly interacts with and is phosphorylated by Dyrk1A. Dyrk1A-mediated phosphorylation at the Thr356 residue inhibits GSK3β activity. Dyrk1A transgenic (TG) mice are lean and resistant to diet-induced obesity, because of reduced fat mass, which shows an inverse correlation with the effect of GSK3β on obesity. This result suggests a potential in vivo association between GSK3β and Dyrk1A regarding the mechanism underlying obesity. The level of phospho-Thr356-GSK3β (pT356-GSK3β was higher in the white adipose tissue (WAT) of Dyrk1A TG mice compared with control mice. GSK3β activity was differentially regulated by phosphorylation at different sites in adipose tissue depending on the type of diet that the mice were fed. Furthermore, overexpression of Dyrk1A suppressed the expression of adipogenic proteins including peroxisome proliferator-activated receptor γ (PPARγ) in 3T3-L1 cells and in young Dyrk1A TG mice fed a chow diet. Taken together, these results reveal a novel regulatory mechanism for GSK3β activity and indicate that overexpression of Dyrk1A may contribute to the obesity-resistant phenotype through phosphorylation and inactivation of GSK3β.
  • Posted in Journal of Biological Chemistry, Publications
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