Role of the SIK2-p35-PJA2 complex in pancreatic β-cell functional compensation (vol 16, pg 234, 2014)

被引：72

作者：

Sakamaki, Jun-Ichi

Fu, Accalia

Reeks, Courtney

Baird, Stephen

Depatie, Chantal

Al Azzabi, Mufida

Bardeesy, Nabeel

Gingras, Anne-Claude

Yee, Siu-Pok

Screaton, Robert A.

机构：

[1] Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa

[2] Department of Biochemistry, Microbiology and Immunology, Department of Cellular and Molecular Medicine, Ottawa

[3] Cancer Center, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston

[4] Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto

[5] Department of Molecular Genetics, University of Toronto, Toronto

[6] Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington

[7] Department of Pediatrics, University of Ottawa, Ottawa

来源：

NATURE CELL BIOLOGY | 2014年 / 16卷 / 03期

基金：

加拿大健康研究院; 日本学术振兴会;

关键词：

D O I：

10.1038/ncb2919

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Energy sensing by the AMP-activated protein kinase (AMPK) is of fundamental importance in cell biology. In the pancreatic beta-cell, AMPK is a central regulator of insulin secretion. The capacity of the beta-cell to increase insulin output is a critical compensatory mechanism in prediabetes, yet its molecular underpinnings are unclear. Here we delineate a complex consisting of the AMPK-related kinase SIK2, the CDK5 activator CDK5R1 (also known as p35) and the E3 ligase PJA2 essential for beta-cell functional compensation. Following glucose stimulation, SIK2 phosphorylates p35 at Ser 91, to trigger its ubiquitylation by PJA2 and promote insulin secretion. Furthermore, SIK2 accumulates in beta-cells in models of metabolic syndrome to permit compensatory secretion; in contrast, beta-cell knockout of SIK2 leads to accumulation of p35 and impaired secretion. This work demonstrates that the SIK2-p35-PJA2 complex is essential for glucose homeostasis and provides a link between p35-CDK5 and the AMPK family in excitable cells.

引用

页码：234 / +

页数：1

共 1 条

[1] Role of the SIK2-p35-PJA2 complex in pancreatic β-cell functional compensation (vol 16, pg 234, 2014) [J].