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    • Numerous stimuli lead to inactivation of

    2022-05-27

    Numerous stimuli lead to inactivation of GSK-3, including Growth Factors such as EGF (Epidermal Growth Factor), PDGF (Platelet-Derived Growth Factor), BDNF (Brain-derived neurotrophic factor), IGF (Insulin-like growth factor) and insulin (Beaulieu et al., 2009, Chen and Russo-Neustadt, 2005, Cohen and Frame, 2001, Siraskar et al., 2011, Stambolic and Woodgett, 1994) and interactions with NF-κB (Beurel and Jope, 2006, Martin et al., 2005, Vines et al., 2006), mTOR (Dong et al., 2005), TGF-β (Clifford et al., 2008) and p38 are known (Thornton et al., 2008). Furthermore, GSK-3 phosphorylates a number of Wnt signaling components, including β-catenin, Axin, APC, and potentially LRPs (Zeng et al., 2005). 1,8-cineol is used in a wide variety of consumables and due to its anti-inflammatory properties, it plays a major role in the treatment of upper and lower airway diseases, like chronic sinusitis and bronchitis, chronic obstructive pulmonary disease (COPD) and NVP-TAE684 synthesis (Bastos et al., 2011, Juergens, 2014, Juergens et al., 2003, Juergens et al., 1998a, Juergens et al., 1998b, Worth et al., 2009, Zhou et al., 2007). Other studies reported anti-nociceptive effects, protective effects and anti-bacterial activity of 1,8-cineol (Mulyaningsih et al., 2011, Santos and Rao, 2000, Santos and Rao, 2001, Santos et al., 2001), but its mode of action is still unclear. In this study we demonstrated for the first time, that 1,8-cineol acts as a potentially inhibitor of the Wnt/β-catenin signaling activity through dephosphorylation of GSK-3 at Ser9/21 and thus contributes to an activation of GSK-3 and consequently to an inactivation/degradation of β-catenin. The increased degradation of β-catenin correlates with a decreased inhibition of GSK3-β, whereas the affected proteins responsible for this mechanism remain unclear. Both, SGK and AKT, were able to phosphorylate the N-terminus of GSK-3, serine-21 on GSK3-α, and serine-9 on the β-isoform (Failor et al., 2007), but were not affected by 1,8-cineol. Therefore, 1,8-cineol could be an new stimuli that lead to a specific dephosphorylation of GSK-3 at Ser9/21, but this has to be further investigated. Furthermore, monoterpenes are commonly known to directly interfere with NF-κB signaling (Salminen et al., 2008). A few years ago, Greiner et al. showed that 1,8-Cineol reduces the nuclear translocation of NF-κB p65 and further transcriptional activity (Greiner et al., 2013). But GSK-3 is also able to modulate NF-κB signaling. Several studies investigated the role of GSK-3 in modulating NF-κB signaling with different results. Therefore, different GSK-3 inhibitors can activate or inhibit NF-κB, depending on experimental conditions and cell types (Arena et al., 1997, Gotschel et al., 2008, Graham et al., 2010, Nemeth et al., 2002). But the rapid effect of GSK-3 on NF-κB suggests a direct role of GSK-3 in NF-κB signaling (Parameswaran et al., 2016).
    Acknowledgments
    Glycogen synthase kinase-3 (GSK-3) was originally discovered due to its role in regulation of glycogen synthase (GS) activity. However, it was soon discovered that GSK-3 had roles in the regulation of many proteins involved in various physiological processes ranging from regulation of cell growth, cancer and neurology. This special issue of will highlight some of the more recent roles discovered regarding GSK-3 and related pathways and illustrate how these critical enzymes affect various biochemical and biological properties. The PI3K/PTEN/AKT/mTORC1/GSK-3 pathway plays essential roles in cellular growth, inflammation, diabetes, metabolism, neurological disorders including Alzheimer's disease (AD), bipolar depression and many other physiological pathways. This pathway and phospholipid signaling has always been an important focus area covered in the and we will include references to some of the key papers published recently in this journal. The critical biochemical regulatory effects of GSK-3 and its diversity of substrates is reviewed concisely in the article by ) in this special issue of the J. This article also describes the critical regulation of GSK-3 by the serine/threonine kinase AKT and the formation of an auto-inhibitory pseudo-substrate motif after AKT-phosphorylation. Importantly the presence of PI3K/AKT-independent pools of GSK-3 are discussed. These PI3K/AKT important pools are important in the regulation of various enzymes and biochemical events such as the control of beta-catenin phosphorylation which is important in WNT signaling, epithelial/mesenchymal transition (EMT) as well as other processes. In addition, the roles of GSK-3 in the priming phosphorylation of various substrates and importance are discussed in this review.