SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB

Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Neuron (Impact Factor: 15.05). 01/2011; 69(1):106-19. DOI: 10.1016/j.neuron.2010.12.004
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The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that salt-inducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca(2+)/calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2(-/-) mice, and ischemic neuronal injury was significantly reduced in the brains of sik2(-)(/-) mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.

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    • "Constitutively active CaMKIV, but not CaMKII, rescues cerebellar granular neurons from KCl deprivationinduced apoptosis (See et al. 2001) as well as the survival of spiral ganglion neurons (Hansen et al. 2003) and chicken motor neurons in the absence of trophic support(Perez-Garcia et al. 2008), while dominant negative CaMKIV blocks the survival promoting effects of 30 mM KCl. It should be noted that CaMKIV regulates a number of downstream transcription and signalling targets, which most recently includes phosphorylation of salt-induced kinase (SIK2), a negative regulator of CREB activity in neurons (Sasaki et al. 2011). Sasaki et al. showed that CaMKIV-phosphorylated sik2 is targeted for degradation and that sik2 À/À mice show decreased ischaemic neuronal injury compared with wild type. "
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    ABSTRACT: NMDA-type glutamate receptors mediate both trophic and excitotoxic signalling in CNS neurons. We have previously shown that blocking NMDAR-PSD95 interactions provides significant protection from excitotoxicity and in vivo ischemia; however the mechanism of neuroprotection is unclear. Here we report that blocking PSD-95 interactions with the Tat-NR2B9c peptide enhances a Ca(2+) -dependent protective pathway converging on CREB activation. We provide evidence that Tat-NR2B9c neuroprotection from oxygen glucose deprivation and NMDA toxicity occurs in parallel with the activation of calmodulin kinase signalling and is dependent on a sustained phosphorylation of the CREB transcription factor and its activator CaMKIV. Tat-NR2B9c-dependent neuroprotection and CREB phosphorylation are blocked by co-application of CaM kinase (KN93 and STO-609) or CREB (KG-501) inhibitors, and by siRNA knockdown of CaMKIV. These results are mirrored in vivo in a rat model of permanent focal ischemia. Tat-NR2B9c application significantly reduces infarct size and causes a selective and sustained elevation in CaMKIV phosphorylation; effects which are blocked by co-administration of KN93. Thus calcium-dependent nuclear signalling via CaMKIV and CREB is critical for neuroprotection via NMDAR-PSD95 blockade, both in vitro and in vivo. This study highlights the importance of maintaining neuronal function following ischemic injury. Future stroke research should target neurotrophic and pro-survival signal pathways in the development of novel neuroprotective strategies. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12176.
    Journal of Neurochemistry 01/2013; 126(2). DOI:10.1111/jnc.12176 · 4.28 Impact Factor
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    • "SIK2 and SIK3. SIK2 is predominantly expressed in adipose tissue and is involved in neuronal survival [6], [7] and in the suppression of melanogenesis in melanocytes [8], [9]. The ubiquitously expressed SIK3 isoform induces chondrocyte differentiation [10] and regulates glucose and lipid metabolism [11]. "
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    ABSTRACT: Substantial evidence supports a role for myocyte enhancer factor 2 (MEF2)-mediated transcription in neuronal survival, differentiation and synaptic function. In developing neurons, it has been shown that MEF2-dependent transcription is regulated by neurotrophins. Despite these observations, little is known about the cellular mechanisms by which neurotrophins activate MEF2 transcriptional activity. In this study, we examined the role of salt-inducible kinase 1 (SIK1), a member of the AMP-activated protein kinase (AMPK) family, in the regulation of MEF2-mediated transcription by the neurotrophin brain-derived neurotrophic factor (BDNF). We show that BDNF increases the expression of SIK1 in primary cultures of rat cortical neurons through the extracellular signal-regulated kinase 1/2 (ERK1/2)-signaling pathway. In addition to inducing SIK1 expression, BDNF triggers the phosphorylation of SIK1 at Thr182 and its translocation from the cytoplasm to the nucleus of cortical neurons. The effects of BDNF on the expression, phosphorylation and, translocation of SIK1 are followed by the phosphorylation and nuclear export of histone deacetylase 5 (HDAC5). Blockade of SIK activity with a low concentration of staurosporine abolished BDNF-induced phosphorylation and nuclear export of HDAC5 in cortical neurons. Importantly, stimulation of HDAC5 phosphorylation and nuclear export by BDNF is accompanied by the activation of MEF2-mediated transcription, an effect that is suppressed by staurosporine. Consistent with these data, BDNF induces the expression of the MEF2 target genes Arc and Nur77, in a staurosporine-sensitive manner. In further support of the role of SIK1 in the regulation of MEF2-dependent transcription by BDNF, we found that expression of wild-type SIK1 or S577A SIK1, a mutated form of SIK1 which is retained in the nucleus of transfected cells, is sufficient to enhance MEF2 transcriptional activity in cortical neurons. Together, these data identify a previously unrecognized mechanism by which SIK1 mediates the activation of MEF2-dependent transcription by BDNF.
    PLoS ONE 01/2013; 8(1):e54545. DOI:10.1371/journal.pone.0054545 · 3.23 Impact Factor
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    • "To examine the specific role of AMPK or SIK in this experiment , we stimulated neurons with bicuculline, and then allowed the neurons to recover in the presence of dorsomorphin dihydrochloride (DM; 20 mM), an inhibitor of both AMPK and SIK activity (Sasaki et al., 2011). DM prolonged CRTC1 presence in the nucleus (Figure S5D), consistent with AMPK or SIK rephosphorylating CRTC1 and promoting rapid nuclear export. "
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    ABSTRACT: Long-lasting changes in synaptic efficacy, such as those underlying long-term memory, require transcription. Activity-dependent transport of synaptically localized transcriptional regulators provides a direct means of coupling synaptic stimulation with changes in transcription. The CREB-regulated transcriptional coactivator (CRTC1), which is required for long-term hippocampal plasticity, binds CREB to potently promote transcription. We show that CRTC1 localizes to synapses in silenced hippocampal neurons but translocates to the nucleus in response to localized synaptic stimulation. Regulated nuclear translocation occurs only in excitatory neurons and requires calcium influx and calcineurin activation. CRTC1 is controlled in a dual fashion with activity regulating CRTC1 nuclear translocation and cAMP modulating its persistence in the nucleus. Neuronal activity triggers a complex change in CRTC1 phosphorylation, suggesting that CRTC1 may link specific types of stimuli to specific changes in gene expression. Together, our results indicate that synapse-to-nuclear transport of CRTC1 dynamically informs the nucleus about synaptic activity.
    Cell 07/2012; 150(1):207-21. DOI:10.1016/j.cell.2012.05.027 · 32.24 Impact Factor
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