SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB

Neuron. 2011 Jan 13;69(1):106-19. doi: 10.1016/j.neuron.2010.12.004.

Abstract

The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that salt-inducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca(2+)/calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2(-/-) mice, and ischemic neuronal injury was significantly reduced in the brains of sik2(-)(/-) mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CREB-Binding Protein / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism
  • Cell Count
  • Cell Hypoxia*
  • Cell Survival*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • DNA, Recombinant
  • Gene Expression
  • Glucose / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs
  • Neurons / metabolism*
  • Oxygen / metabolism
  • Phosphorylation*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Transcription Factors / metabolism*

Substances

  • Crtc1 protein, mouse
  • DNA, Recombinant
  • MicroRNAs
  • Transcription Factors
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • salt-inducible kinase-2, mouse
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Glucose
  • Oxygen