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: 15.98). 01/2011; 69(1):106-19. DOI: 10.1016/j.neuron.2010.12.004
Source: PubMed

ABSTRACT 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.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: CREB is a pivotal mediator of activity-regulated gene transcription that underlies memory formation and allocation. The contribution of a key CREB cofactor, CREB-regulated transcription coactivator 1 (CRTC1), has, however, remained elusive. Here we show that several constitutive kinase pathways and an activity-regulated phosphatase, calcineurin, converge to determine the nucleocytoplasmic shuttling of CRTC1. This, in turn, triggered an activity-dependent association of CRTC1 with CREB-dependent regulatory elements found on IEG promoters. Forced expression of nuclear CRTC1 in hippocampal neurons activated CREB-dependent transcription, and was sufficient to enhance contextual fear memory. Surprisingly, during contextual fear conditioning, we found evidence of nuclear recruitment of endogenous CRTC1 only in the basolateral amygdala, and not in the hippocampus. Consistently, CRTC1 knockdown in the amygdala, but not in the hippocampus, significantly attenuated fear memory. Thus, CRTC1 has a wide impact on CREB-dependent memory processes, but fine-tunes CREB output in a region-specific manner.
    Neuron 10/2014; 84(1):92–106. DOI:10.1016/j.neuron.2014.08.049 · 15.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PPP2R2C encodes a gamma isoform of the regulatory subunit B55 subfamily consisting PP2A heterotrimeric with A and C subunits. Currently, the precise functions of B55gamma in cancer are still under investigating. In this project, we reported a novel function of B55gamma in the regulation of glucose metabolism in Glioma cells. Western blot and immunoprecipitation were performed to determine protein expression and interaction. Cell viability was measured by Typan Blue staining and direct cell counting using hematocytometer. siRNA technology was used to down regulate protein expression. Glucose uptake and lactate product were suppressed by overexpression of B55gamma in Glioma cells. In addition, cancer cells with larger amount of B55gamma showed higher survival advantages in response to glucose starvation through the dephosphorylation of S6K. From proteomic analysis, we found B55gamma binds with and up regulates SIK2 through the stabilization of SIK2 protein which is required for the B55gamma-mediated suppression of S6K pathway. Knocking down of SIK2 in B55gamma over expressing cells recovered the phosphorylation of S6K. In summary, our project will provide novel insight into the design and development of therapeutic strategies to target the B55gamma-mediated glucose metabolism for the treatment of human brain tumor patients.
    Cancer Cell International 12/2015; 15(1). DOI:10.1186/s12935-015-0164-6 · 1.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclic AMP promotes chronic expression of target genes mainly by protein kinase A-dependent activation of CREB transcription factor machineries in the metabolic tissues. Here we wanted to elaborate whether CREB regulated transcription factor (CRTC) 2 and its negative regulator salt inducible kinase (SIK) 2 are involved in the transcriptional control of the metabolic pathway in adipocytes. SIK2 knockout mice exhibited higher blood glucose levels that were associated with impaired glucose and insulin tolerance. Hypertriglyceridemia was apparent in SIK2 knockout mice, mainly due to the increased lipolysis from white adipocytes and the decreased fatty acid uptake in the peripheral tissues. Investigation of white adipocytes revealed the increases in fat cell size and macrophage infiltration, which could be linked to the metabolic anomaly that is associated in these mice. Interestingly, SIK2 knockout promoted the enhancement in CRTC2-CREB transcriptional pathway in white adipocytes. Increased expression of ATF3 and subsequent downregulation of GLUT4 expression and reduction in high molecular weight adiponectin levels in the plasma, leading to the reduced glucose uptake in the muscle and white adipocytes. The effect of SIK2-dependent regulation of adipocyte metabolism was further confirmed by in vitro cell cultures of 3T3 L1 adipocytes and the differentiated preadipocytes from the SIK2 or CRTC2 knockout mice. Collectively, these data suggest that SIK2 is critical in regulating whole body glucose metabolism primarily by controlling the CRTC2-CREB function of the white adipocytes.
    Diabetes 06/2014; 63(11). DOI:10.2337/db13-1423 · 8.47 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014