SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Emma Henriksson, Johanna Säll, Amélie Gormand, Sebastian Wasserstrom, Nicholas A. Morrice, Andreas M. Fritzen, Marc Foretz, David G. Campbell, Kei Sakamoto, Mikael Ekelund, Eva Degerman, Karin G. Stenkula, Olga Göransson (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)
163 Downloads (Pure)

Abstract

Salt-inducible kinase 2 (SIK2) is an AMP-activated protein kinase (AMPK) related kinase abundantly expressed in adipose tissue. Our aim was to identify molecular targets and functions of SIK2 in adipocytes, and to address the role of PKA-mediated phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2), CRTC3 and class IIa histone deacetylase 4 (HDAC4). Furthermore, CRTC2, CRTC3, HDAC4 and protein phosphatase 2A (PP2A) interacted with SIK2, and the binding of CRTCs and PP2A to wild-type but not Ser358Ala SIK2, was reduced by cAMP elevation. Silencing of SIK2 resulted in reduced GLUT4 (also known as SLC2A4) protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased levels of GLUT4. Overexpression or pharmacological inhibition of SIK2 resulted in increased and decreased glucose uptake, respectively. We also describe a SIK2-CRTC2-HDAC4 pathway and its regulation in human adipocytes, strengthening the physiological relevance of our findings. Collectively, we demonstrate that SIK2 acts directly on CRTC2, CRTC3 and HDAC4, and that the cAMP-PKA pathway reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 increases GLUT4 levels and glucose uptake in adipocytes.

Original languageEnglish
Pages (from-to)472-486
Number of pages15
JournalJournal of Cell Science
Volume128
Issue number3
Early online date3 Dec 2014
DOIs
Publication statusPublished - 29 Jan 2015

Keywords

  • Adipocyte
  • CRTC2
  • CRTC3
  • Glucose uptake
  • HDAC4
  • PP2A
  • SIK2

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