Role of the SIK2-p35-PJA2 complex in pancreatic β-cell functional compensation

Nat Cell Biol. 2014 Mar;16(3):234-44. doi: 10.1038/ncb2919.


Energy sensing by the AMP-activated protein kinase (AMPK) is of fundamental importance in cell biology. In the pancreatic β-cell, AMPK is a central regulator of insulin secretion. The capacity of the β-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 β-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 β-cells in models of metabolic syndrome to permit compensatory secretion; in contrast, β-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling
  • Female
  • Glucose / physiology
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology*
  • Male
  • Membrane Potentials
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation
  • Phosphotransferases / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • Cdk5r1 protein, mouse
  • Insulin
  • PJA2 protein, mouse
  • Ubiquitin-Protein Ligases
  • Phosphotransferases
  • salt-inducible kinase-2, mouse
  • Protein Serine-Threonine Kinases
  • Glucose