title: p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis.
abstract: Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.
authors: Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors: Jaemin
authors: J
authors: Lee
authors: Cheng
authors: C
authors: Sun
authors: Yingjiang
authors: Y
authors: Zhou
authors: Justin
authors: J
authors: Lee
authors: Deniz
authors: D
authors: Gokalp
authors: Hilde
authors: H
authors: Herrema
authors: Sang Won
authors: SW
authors: Park
authors: Roger J
authors: RJ
authors: Davis
authors: Umut
authors: U
authors: Ozcan
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000502:physiology*; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D055786:Gene Knockout Techniques; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000235:genetics; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D010766:Phosphorylation; D000071701:Regulatory Factor X Transcription Factors; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482567:Map2k6 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases