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p38 MAPKāmediated regulation of Xbp1s is crucial for glucose homeostasis
- Source :
- Nature Medicine. 17:1251-1260
- Publication Year :
- 2011
- Publisher :
- Springer Science and Business Media LLC, 2011.
-
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.
- Subjects :
- Kinase
Endoplasmic reticulum
p38 mitogen-activated protein kinases
Mitogen-activated protein kinase
biology.protein
Glucose homeostasis
MAP Kinase Kinase 3
General Medicine
Biology
Mitogen-activated protein kinase kinase
Protein kinase A
General Biochemistry, Genetics and Molecular Biology
Cell biology
Subjects
Details
- ISSN :
- 1546170X and 10788956
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Nature Medicine
- Accession number :
- edsair.doi...........409fc54357d7f5e21db7006cb6ec2e1f