PT  - JOURNAL ARTICLE
AU  - Henriksson, Emma
AU  - Säll, Johanna
AU  - Gormand, Amélie
AU  - Wasserstrom, Sebastian
AU  - Morrice, Nicholas A.
AU  - Fritzen, Andreas M.
AU  - Foretz, Marc
AU  - Campbell, David G.
AU  - Sakamoto, Kei
AU  - Ekelund, Mikael
AU  - Degerman, Eva
AU  - Stenkula, Karin G.
AU  - Göransson, Olga
TI  - SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes
AID  - 10.1242/jcs.153932
DP  - 2015 Feb 01
TA  - Journal of Cell Science
PG  - 472--486
VI  - 128
IP  - 3
4099  - http://jcs.biologists.org/content/128/3/472.short
4100  - http://jcs.biologists.org/content/128/3/472.full
SO  - J. Cell Sci.2015 Feb 01; 128
AB  - 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.