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.
authors.forename: Emma
authors.initials: E
authors.lastname: Henriksson
authors.forename: Johanna
authors.initials: J
authors.lastname: Säll
authors.forename: Amélie
authors.initials: A
authors.lastname: Gormand
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wasserstrom
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Morrice
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Fritzen
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: David G
authors.initials: DG
authors.lastname: Campbell
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Mikael
authors.initials: M
authors.lastname: Ekelund
authors.forename: Eva
authors.initials: E
authors.lastname: Degerman
authors.forename: Karin G
authors.initials: KG
authors.lastname: Stenkula
authors.forename: Olga
authors.initials: O
authors.lastname: Göransson
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C555318:CRTC3 protein, mouse; C504923:Crtc2 protein, mouse; D051275:Glucose Transporter Type 4; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D000242:Cyclic AMP; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D005947:Glucose