SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Emma Henriksson; Johanna Säll; Amélie Gormand; Sebastian Wasserstrom; Nicholas A Morrice; Andreas Mæchel Fritzen; Marc Foretz; David G Campbell; Kei Sakamoto; Mikael Ekelund; Eva Degerman; Karin G Stenkula; Olga Göransson

doi:10.1242/jcs.153932

SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Emma Henriksson, Johanna Säll, Amélie Gormand, Sebastian Wasserstrom, Nicholas A Morrice, Andreas Mæchel Fritzen, Marc Foretz, David G Campbell, Kei Sakamoto, Mikael Ekelund, Eva Degerman, Karin G Stenkula, Olga Göransson

The August Krogh Section for Molecular Physiology

56 Citations (Scopus)

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.

Original language	English
Journal	Journal of Cell Science
Volume	128
Issue number	3
Pages (from-to)	472-486
Number of pages	15
ISSN	0021-9533
DOIs	https://doi.org/10.1242/jcs.153932
Publication status	Published - 2015

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title = "SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes",

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 = "Emma Henriksson and Johanna S{\"a}ll and Am{\'e}lie Gormand and Sebastian Wasserstrom and Morrice, {Nicholas A} and Fritzen, {Andreas M{\ae}chel} and Marc Foretz and Campbell, {David G} and Kei Sakamoto and Mikael Ekelund and Eva Degerman and Stenkula, {Karin G} and Olga G{\"o}ransson",

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year = "2015",

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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 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.

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.

U2 - 10.1242/jcs.153932

DO - 10.1242/jcs.153932

M3 - Journal article

C2 - 25472719

SN - 0021-9533

VL - 128

SP - 472

EP - 486

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 3

ER -

SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Abstract

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