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  • br GSK The GSK family is highly conserved throughout evoluti

    2022-01-18


    GSK-3 The GSK-3 family is highly conserved throughout evolution and is encoded by two genes, GSK-3α and GSK-3β, which are located in chromosomes 19q13.2 and 3q13.3 in human, respectively. Both GSK-3α and GSK-3β proteins exist in a variety of tissues with the highest levels found in zingerone [1], [2]. Although the homology of GSK-3α (51kDa) and GSK-3β (47kDa) is approximately 98% in the catalytic domain, the overall homology is approximately 85%, because of the differences in their C- and N-termini [7]. GSK-3 activity is generally high in resting cells and it is inhibited in response to cellular signaling mediated by growth factors, cytokines and hormones via phosphorylation of Ser21 in GSK-3α and Ser9 in GSK-3β [1], [2]. The homozygous knock out of GSK-3β (GSK-3β−/−) mice yields an embryonic-lethal phenotype because of hepatic apoptosis or a cardiac patterning defect [2], [8], [9]. On the other hand, the homozygous knock out of GSK-3α (GSK-3α−/−) mice are viable, fertile and display a body mass similar to wild-type littermates [2], [10]. These findings suggest that the function of these two isozymes is not completely similar. However, as it has been reported that there is a very high level of functional redundancy with respect to the GSK-3 isozymes in the canonical Wnt signaling pathway [11], their functions might be closely related and both isozymes might play very similar roles in several signaling pathways. There is also an alternatively spliced GSK-3β variant that encodes GSK-3β2, which has a 13-residue insert in the kinase domain and is the neuron-specific isoform [12]. It has been reported that GSK-3β2 has lower phosphorylation activity toward tau than GSK-3β [13].
    GSK-3 and its role in signaling pathways Although the mechanisms regulating GSK-3 localization are not fully understood, GSK-3 is known to be located in cytoplasm, nucleus, and mitochondria. It has been reported that nuclear GSK-3 plays important roles during apoptosis and mitochondrial GSK-3 contributes to the regulation of energy metabolism [2], [14]. However, because GSK-3 is considered to be mainly located in cytoplasm, this review focuses on the roles of GSK-3 in cytoplasm and summarizes its roles in the insulin, Wnt/β-catenin and Hedgehog signaling pathways.
    GSK-3 and diseases Because GSK-3 plays central roles in a number of important signaling pathways, malfunction of GSK-3 is implicated in the pathogenesis of a number of diseases, including nervous system disorders, diabetes, inflammation, bone formation, cancer and heart failure (Fig. 2). Indeed, GSK-3β gene polymorphisms related to disease are reported. For example, the SNP rs334558 (−50 T/C), located in the promoter region and the T allele showing greater transcription activity than C allele, has been reported to be linked with nervous system disorders [27], [28]. The T allele of the SNP rs6438552, located within intron 5, is associated with increased GSK-3β transcripts that lack exons 9 and 11, thereby enhancing the phosphorylation activity of this kinase. This SNP has been reported to be linked with Parkinson's disease [29] and cancer [30]. No gene polymorphisms related to disease are reported for GSK-3α at present.
    Modulators of GSK-3 activity
    Conclusions Many pharmaceutical companies are interested in GSK-3 as a target for the development of new drugs. Currently one GSK-3 inhibitor is in a phase II clinical trial for the treatment of AD and progressive supranuclear palsy. Diabetes, inflammation and bone disease could also be targets for treatment using a GSK-3 inhibitor. However, the development of GSK-3 inhibitors is challenging because of the importance of GSK-3 in zingerone glucose metabolism and the possible effects of GSK-3 inhibition on cancer and cardiac disease, especially for long-term use. Indeed, cardiac problems have been reported with lithium long-term use [103]. Although the long-term use of lithium for the treatment of bipolar disease has not been associated with an increased risk of cancer [104], the therapeutic concentration range of lithium in serum (approximately 0.5–1.5mM) is slightly lower than its IC50 for GSK-3 (approximately 2mM) and it has also been reported that lithium did not potently inhibit GSK-3 at concentrations found in serum taken from treated bipolar patients [105]. Therefore, the possibility of side effects using a specific and potent GSK-3 inhibitor, especially in terms of risk for cancer and cardiac disease, should be carefully considered.