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SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Henriksson, Emma LU ; Sernevi Säll, Johanna LU ; Gormand, Amelie LU ; Wasserstrom, Sebastian LU ; Morrice, Nicholas A.; Fritzen, Andreas M.; Foretz, Marc; Campbell, David G.; Sakamoto, Kei and Ekelund, Mikael LU , et al. (2015) In Journal of Cell Science 128(3). p.472-486
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... (More)
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. (Less)
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keywords
SIK2, Adipocyte, CRTC2, CRTC3, HDAC4, PP2A, Glucose uptake
in
Journal of Cell Science
volume
128
issue
3
pages
472 - 486
publisher
The Company of Biologists Ltd
external identifiers
  • wos:000349017900006
  • scopus:84922161593
ISSN
0021-9533
DOI
10.1242/jcs.153932
language
English
LU publication?
yes
id
603ddd36-db24-40ac-8288-bde125fb5ec6 (old id 5187250)
date added to LUP
2015-04-01 07:31:35
date last changed
2017-10-29 03:23:48
@article{603ddd36-db24-40ac-8288-bde125fb5ec6,
  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.},
  author       = {Henriksson, Emma and Sernevi Säll, Johanna and Gormand, Amelie and Wasserstrom, Sebastian and Morrice, Nicholas A. and Fritzen, Andreas M. and Foretz, Marc and Campbell, David G. and Sakamoto, Kei and Ekelund, Mikael and Degerman, Eva and Stenkula, Karin and Göransson, Olga},
  issn         = {0021-9533},
  keyword      = {SIK2,Adipocyte,CRTC2,CRTC3,HDAC4,PP2A,Glucose uptake},
  language     = {eng},
  number       = {3},
  pages        = {472--486},
  publisher    = {The Company of Biologists Ltd},
  series       = {Journal of Cell Science},
  title        = {SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes},
  url          = {http://dx.doi.org/10.1242/jcs.153932},
  volume       = {128},
  year         = {2015},
}