cAMP-elevation mediated by β-adrenergic stimulation inhibits salt-inducible kinase (SIK) 3 activity in adipocytes

Berggreen, Christine; Jones, Helena A.; Morrice, Nicholas A.; Göransson, Olga

doi:10.1016/j.cellsig.2012.05.001

Cited by 38 publications

(43 citation statements)

References 29 publications

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“…This suggests that SIK2 accounts for the portion of CRTC and HDAC phosphorylation that is inhibited by cAMP. However, the SIK3 isoform is also regulated by cAMP-induced phosphorylation in adipocytes, resulting in reduced kinase activity (Berggreen et al, 2012), and could potentially also phosphorylate CRTCs and class IIa HDACs in adipocytes. Additional kinases involved in the residual phosphorylation of CRTC2 and HDAC4 are still to be determined, but might include MARK2, AMPK and/or SIK1.…”

Section: Discussionmentioning

confidence: 99%

Salt-inducible kinase 2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Henriksson

Säll

Gormand

et al. 2014

Journal of Cell Science

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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.

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Section: Discussionmentioning

confidence: 99%

Salt-inducible kinase 2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Henriksson

Säll

Gormand

et al. 2014

Journal of Cell Science

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“…cAMP sensitivity of SIK3 and SIK1 depends upon two PKA sites that mediate 14-3-3 protein interaction Although all three SIKs have been found to associate with 14-3-3 proteins, a potential role for cAMP/PKA in modulating this interaction has only been suggested for SIK2 and SIK3 [27,28,32,33]. In addition, only SIK3's activity appears to be repressed by 14-3-3s in vitro [27].…”

Section: Sik Activity Is Inhibited By Camp Signalingmentioning

confidence: 99%

“…In addition, only SIK3's activity appears to be repressed by 14-3-3s in vitro [27]. Because PKA-mediated phosphorylation has been shown to interfere with the intracellular activity of SIKs, we systematically evaluated whether PKA regulates the activity of all three SIKs by controlling their association with 14-3-3s [10].…”

Section: Sik Activity Is Inhibited By Camp Signalingmentioning

confidence: 99%

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14‐3‐3 proteins mediate inhibitory effects of cAMP on salt‐inducible kinases (SIKs)

2018

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The salt‐inducible kinase (SIK) family regulates cellular gene expression via the phosphorylation of cAMP‐regulated transcriptional coactivators (CRTCs) and class IIA histone deacetylases, which are sequestered in the cytoplasm by phosphorylation‐dependent 14‐3‐3 interactions. SIK activity toward these substrates is inhibited by increases in cAMP signaling, although the underlying mechanism is unclear. Here, we show that the protein kinase A (PKA)‐dependent phosphorylation of SIKs inhibits their catalytic activity by inducing 14‐3‐3 protein binding. SIK1 and SIK3 contain two functional PKA/14‐3‐3 sites, while SIK2 has four. In keeping with the dimeric nature of 14‐3‐3s, the presence of multiple binding sites within target proteins dramatically increases binding affinity. As a result, loss of a single 14‐3‐3‐binding site in SIK1 and SIK3 abolished 14‐3‐3 association and rendered them insensitive to cAMP. In contrast, mutation of three sites in SIK2 was necessary to fully block cAMP regulation. Superimposed on the effects of PKA phosphorylation and 14‐3‐3 association, an evolutionary conserved domain in SIK1 and SIK2 (the so called RK‐rich region; 595–624 in hSIK2) is also required for the inhibition of SIK2 activity. Collectively, these results point to a dual role for 14‐3‐3 proteins in repressing a family of Ser/Thr kinases as well as their substrates.

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“…3B). The analogous site in SIK3(T469) was recently shown to be phosphorylated by PKA in adipocytes (28), and SIK2(T484) has been implicated in degradation of SIK2 induced by calcium-dependent kinases (29). We mutated these sites alone or in combination in catalytically inactive SIK1(K56M) (kinase dead, or "KD") to prevent autophosphorylation and tested phosphorylation of SIK1 by recombinant PKA in vitro.…”

Section: Sik1 Ismentioning

confidence: 99%

Regulation of SIK1 abundance and stability is critical for myogenesis

Stewart¹,

Akhmedov²,

Robb³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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cAMP signaling can both promote and inhibit myogenic differentiation, but little is known about the mechanisms mediating promyogenic effects of cAMP. We previously demonstrated that the cAMP response element-binding protein (CREB) transcriptional target salt-inducible kinase 1 (SIK1) promotes MEF2 activity in myocytes via phosphorylation of class II histone deacetylase proteins (HDACs). However, it was unknown whether SIK1 couples cAMP signaling to the HDAC-MEF2 pathway during myogenesis and how this response could specifically occur in differentiating muscle cells. To address these questions, we explored SIK1 regulation and function in muscle precursor cells before and during myogenic differentiation. We found that in primary myogenic progenitor cells exposed to cAMP-inducing agents, Sik1 transcription is induced, but the protein is rapidly degraded by the proteasome. By contrast, sustained cAMP signaling extends the half-life of SIK1 in part by phosphorylation of Thr475, a previously uncharacterized site that we show can be phosphorylated by PKA in cell-free assays. We also identified a functional PEST domain near Thr475 that contributes to SIK1 degradation. During differentiation of primary myogenic progenitor cells, when PKA activity has been shown to increase, we observe elevated Sik1 transcripts as well as marked accumulation and stabilization of SIK1 protein. Depletion of Sik1 in primary muscle precursor cells profoundly impairs MEF2 protein accumulation and myogenic differentiation. Our findings support an emerging model in which SIK1 integrates cAMP signaling with the myogenic program to support appropriate timing of differentiation. M yoblast differentiation is driven by a transcriptional cascade that is subject to precise temporal control during development as well as after acute muscle injury (1). The second messenger cAMP and its primary effector PKA are known to contribute to myoblast proliferation in the developing dermomyotome (2), to promote migration and fusion of muscle precursor cells (3, 4), and to exert potent anabolic effects on adult skeletal muscle (5). During differentiation of myoblasts ex vivo, intracellular cAMP peaks transiently before cell-cell fusion (6, 7), and PKA signaling is required for expression of differentiation markers in cultured myoblasts (8) and in mouse embryos (2). However, sustained cAMP-PKA signaling prevents myogenic differentiation, in part through inhibition of basic helix-loop-helix and MADS transcription factors (9-11). The mechanisms by which a transient peak of cAMP promotes myoblast differentiation are still poorly understood. Because ligands that induce cAMP production promote muscle regeneration (5), it is important to identify promyogenic cAMP signaling effectors.The transcription factor CREB (cAMP response elementbinding protein) is a key effector of cAMP-PKA in many cell types (12). CREB phosphorylation is induced during early stages of vertebrate myogenesis (2, 13), and CREB activity is required in mice for dermomyotome development (2). We previously...

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cAMP-elevation mediated by β-adrenergic stimulation inhibits salt-inducible kinase (SIK) 3 activity in adipocytes

Cited by 38 publications

References 29 publications

Salt-inducible kinase 2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

Salt-inducible kinase 2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

14‐3‐3 proteins mediate inhibitory effects of cAMP on salt‐inducible kinases (SIKs)

Regulation of SIK1 abundance and stability is critical for myogenesis

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