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: 15.77). 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 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA- and Ca(++)-regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and FFSS both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by FFSS that promote CREB-dependent gene expression in this tissue.
    Genes & development 01/2014; 28(2):127-39. · 12.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of primary sclerosing cholangitis (PSC) involves heritable factors. This review summarizes the recent genetic studies and discusses the implications of identified risk loci. A total of 16 PSC susceptibility loci have been identified in genome-wide association studies and related study designs. At least 33 additional loci are involved in what is increasingly acknowledged to represent a general pool of genetic risk loci for immune-mediated diseases. One important group of genes is part of well characterized immune pathways (e.g. interleukin 2 signaling), whereas for other loci the relationship to PSC pathophysiology is less evident. Importantly, the loci collectively account for only 7.3% of overall PSC liability, thus pointing to a large contribution from environmental factors to PSC development. The individual PSC risk genes cannot be interpreted within a simple cause-effect model used for monogenic traits, but need to be explored for their individual biological correlates, preferably in a disease context. To some extent, as exemplified for the human leukocyte antigen and FUT2 associations, genetic findings may guide the discovery of interacting and co-occuring environmental susceptibility factors. Multiple PSC susceptibility loci are now available for exploration in experimental model systems and patient-centered research.
    Current opinion in gastroenterology 02/2014; · 4.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Correct regulation of insulin secretion by the pancreas is crucial for organismal function and survival. The AMPK-related kinase SIK2 (salt-inducible kinase 2) is now shown to be stabilized in pancreatic β-cells following glucose stimulation, leading to improved systemic glucose homeostasis by regulating cellular calcium flux and insulin secretion.
    Nature Cell Biology 02/2014; 16(3):210-2. · 20.06 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014