SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5187250
- author
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- 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
- pmid:25472719
- scopus:84922161593
- ISSN
- 0021-9533
- DOI
- 10.1242/jcs.153932
- project
- Salt-inducible kinases in adipose tissue
- language
- English
- LU publication?
- yes
- id
- 603ddd36-db24-40ac-8288-bde125fb5ec6 (old id 5187250)
- date added to LUP
- 2016-04-01 11:16:40
- date last changed
- 2024-04-08 03:50:32
@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 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}}, keywords = {{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}}, doi = {{10.1242/jcs.153932}}, volume = {{128}}, year = {{2015}}, }