SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes
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SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes. / Henriksson, Emma; Säll, Johanna; Gormand, Amélie; Wasserstrom, Sebastian; Morrice, Nicholas A; Fritzen, Andreas Mæchel; Foretz, Marc; Campbell, David G; Sakamoto, Kei; Ekelund, Mikael; Degerman, Eva; Stenkula, Karin G; Göransson, Olga.
In: Journal of Cell Science, Vol. 128, No. 3, 2015, p. 472-486.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes
AU - Henriksson, Emma
AU - Säll, Johanna
AU - Gormand, Amélie
AU - Wasserstrom, Sebastian
AU - Morrice, Nicholas A
AU - Fritzen, Andreas Mæchel
AU - Foretz, Marc
AU - Campbell, David G
AU - Sakamoto, Kei
AU - Ekelund, Mikael
AU - Degerman, Eva
AU - Stenkula, Karin G
AU - Göransson, Olga
N1 - CURIS 2015 NEXS 053
PY - 2015
Y1 - 2015
N2 - Salt-inducible kinase 2 (SIK2) is an 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-phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2) and -3, 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 protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased GLUT4. Over-expression 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 cAMP/PKA reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 promotes GLUT4 levels and glucose uptake in adipocytes.
AB - Salt-inducible kinase 2 (SIK2) is an 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-phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2) and -3, 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 protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased GLUT4. Over-expression 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 cAMP/PKA reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 promotes GLUT4 levels and glucose uptake in adipocytes.
U2 - 10.1242/jcs.153932
DO - 10.1242/jcs.153932
M3 - Journal article
C2 - 25472719
VL - 128
SP - 472
EP - 486
JO - Journal of Cell Science
JF - Journal of Cell Science
SN - 0021-9533
IS - 3
ER -
ID: 129784513