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SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Author:
  • Emma Henriksson
  • Johanna Sernevi Säll
  • Amelie Gormand
  • Sebastian Wasserstrom
  • Nicholas A. Morrice
  • Andreas M. Fritzen
  • Marc Foretz
  • David G. Campbell
  • Kei Sakamoto
  • Mikael Ekelund
  • Eva Degerman
  • Karin Stenkula
  • Olga Göransson
Publishing year: 2015
Language: English
Pages: 472-486
Publication/Series: Journal of Cell Science
Volume: 128
Issue: 3
Document type: Journal article
Publisher: The Company of Biologists Ltd

Abstract english

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.

Keywords

  • Cell and Molecular Biology
  • SIK2
  • Adipocyte
  • CRTC2
  • CRTC3
  • HDAC4
  • PP2A
  • Glucose uptake

Other

Published
  • Protein Phosphorylation
  • Glucose Transport and Protein Trafficking
  • Insulin Signal Transduction
  • ISSN: 0021-9533
Eva Degerman
E-mail: eva [dot] degerman [at] med [dot] lu [dot] se

Professor

Insulin Signal Transduction

+46 46 222 85 83

+46 70 885 83 62

BMC C1121b

66

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00