Journal
NATURE CELL BIOLOGY
Volume 16, Issue 3, Pages 234-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2919
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Funding
- Canadian Diabetes Association [OG-3-11-3328-RS]
- Canadian Institutes of Health Research (CIHR) [MOP-97772]
- Canadian Foundation for Innovation (CFI)
- CIHR [MOP-84314]
- Japan Society for the Promotion of Science [10J00366]
- Canadian Diabetes Studentship
- Grants-in-Aid for Scientific Research [10J00366] Funding Source: KAKEN
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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.
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