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Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis.

ABSTRACT: Mechanisms regulating the nuclear localization of glycogen synthase kinase-3beta (GSK3beta) remained enigmatic despite the crucial regulation by nuclear GSK3beta of important cellular functions. These include regulation of gene expression, cell cycle progression, and apoptosis, achieved by the phosphorylation by GSK3 of nuclear substrates (e.g. numerous transcription factors). We resolved this mechanism by identifying a bipartite nuclear localization sequence (NLS) that is necessary for the nuclear accumulation of GSK3beta and is sufficient to drive yellow fluorescent protein into the nucleus. Despite the NLS, most GSK3beta is cytosolic, sequestered in protein complexes that, although still mobile in the cytosol, block the NLS. Conditions promoting nuclear translocation of GSK3beta release it from cytosolic complexes, allowing the NLS to direct nuclear import. Using this information to prepare a nucleus-excluded active GSK3 construct, we found that the antiapoptotic effect of GSK3beta in tumor necrosis factor-induced apoptosis is mediated by cytosolic, not nuclear, GSK3beta. Identification of a GSK3beta NLS allows new strategies to decipher and manipulate its subcellular actions regulating gene expression and apoptosis and its involvement in diseases.

SUBMITTER: Meares GP

PROVIDER: S-EPMC1948884 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis.

Meares Gordon P GP Jope Richard S RS

The Journal of biological chemistry 20070416 23

Mechanisms regulating the nuclear localization of glycogen synthase kinase-3beta (GSK3beta) remained enigmatic despite the crucial regulation by nuclear GSK3beta of important cellular functions. These include regulation of gene expression, cell cycle progression, and apoptosis, achieved by the phosphorylation by GSK3 of nuclear substrates (e.g. numerous transcription factors). We resolved this mechanism by identifying a bipartite nuclear localization sequence (NLS) that is necessary for the nucl ...[more]

PMID: 17438332

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Project description:Glycogen synthase kinase-3 (GSK3) is a constitutively active protein kinase that is involved in neuronal regulation and is a potential pharmacological target of neurological disorders. We found previously that GSK3? selectively interacts with 5-hydroxytryptamine-1B receptors (5-HT1BR) that have important functions in serotonin neurotransmission and behavior. In this study, we provide new information supporting the importance of GSK3? in 5-HT1BR-regulated signaling, physiological function, and behaviors. Using molecular, biochemical, pharmacological, and behavioral approaches, we tested 5-HT1BR's interaction with G(i)?(2) and ?-arrestin2 and 5-HT1BR-regulated signaling in cells, serotonin release in mouse cerebral cortical slices, and behaviors in wild-type and ?-arrestin2 knockout mice. Molecular ablation of GSK3? and GSK3 inhibitors abolished serotonin-induced change of 5-HT1BR coupling to G(i)?(2) and associated signaling but had no effect on serotonin-induced recruitment of ?-arrestin2 to 5-HT1BR. This effect is specific for 5-HT1BR because GSK3 inhibitors did not change the interaction between serotonin 1A receptors and G(i)?(2). Two GSK3 inhibitors, N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418) and 3-(5-bromo-1-methyl-1H-indol-3-yl)-4-(benzofuran-3-yl)pyrrole-2,5-dione (BIP-135), efficiently abolished the inhibitory effect of the 5-HT1BR agonist anpirtoline on serotonin release in mouse cerebral cortical slices. GSK3 inhibitors also facilitated the 5-HT1BR agonist anpirtoline-induced behavioral effect in the tail suspension test but spared anpirtoline-induced locomotor activity. These results suggest that GSK3? is a functional selective modulator of 5-HT1BR-regulated signaling, and GSK3 inhibitors fine-tune the physiological and behavioral actions of 5-HT1BR. Future studies may elucidate the significant roles of GSK3 in serotonin neurotransmission and implications of GSK3 inhibitors as functional selective modulators of 5-HT1BR.

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Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis.

Publications

Resolution of the nuclear localization mechanism of glycogen synthase kinase-3: functional effects in apoptosis.

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