title: Phosphorylation and inactivation of glycogen synthase kinase 3β (GSK3β) by dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A).
abstract: 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 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 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 Thr(356) 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 Thr(P)(356)-GSK3β was higher in the white adipose tissue 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 the mice were fed. Furthermore, overexpression of Dyrk1A suppressed the expression of adipogenic proteins, including peroxisome proliferator-activated receptor γ, 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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, the Institute for Brain Science and Technology, Inje University, Busan 614-735, Korea.
authors.forename: Woo-Joo
authors.initials: WJ
authors.lastname: Song
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, the Institute for Brain Science and Technology, Inje University, Busan 614-735, Korea.
authors.forename: Eun-Ah Christine
authors.initials: EA
authors.lastname: Song
authors.affiliation: the Institute for Brain Science and Technology, Inje University, Busan 614-735, Korea.
authors.forename: Min-Su
authors.initials: MS
authors.lastname: Jung
authors.affiliation: the Institute for Brain Science and Technology, Inje University, Busan 614-735, Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Choi
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine.
authors.forename: Hyung-Hwan
authors.initials: HH
authors.lastname: Baik
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine.
authors.forename: Byung Kwan
authors.initials: BK
authors.lastname: Jin
authors.affiliation: Department of Oral Biochemistry and Molecular Biology, School of Dentistry, and Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701, Korea and.
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, the Institute for Brain Science and Technology, Inje University, Busan 614-735, Korea sulchung@khu.ac.kr sulchung2@gmail.com.
authors.forename: Sul-Hee
authors.initials: SH
authors.lastname: Chung
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology*; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013912:Threonine / Q000737:chemistry; D000097603:Dyrk Kinases
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D013912:Threonine; D000097603:Dyrk Kinases; C000605507:Gsk3b protein, mouse
keywords: Dyrk1A; Enzyme Inactivation; Glycogen Synthase Kinase 3 (GSK-3); Obesity; Phosphorylation; Serine/Threonine Protein Kinase