| First Author | Sakamaki J | Year | 2014 |
| Journal | Nat Cell Biol | Volume | 16 |
| Issue | 3 | Pages | 234-44 |
| PubMed ID | 24561619 | Mgi Jnum | J:212985 |
| Mgi Id | MGI:5582660 | Doi | 10.1038/ncb2919 |
| Citation | Sakamaki J, et al. (2014) Role of the SIK2-p35-PJA2 complex in pancreatic beta-cell functional compensation. Nat Cell Biol 16(3):234-44 |
| abstractText | 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. |
