GSK-3 – at the crossroads of cell death and survival

Maurer, Ulrich; Preiss, Florian; Brauns-Schubert, Prisca; Schlicher, Lisa; Charvet, Céline

doi:10.1242/jcs.138057

Cited by 156 publications

(139 citation statements)

References 126 publications

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“…GSK3β phosphorylates many substrate proteins to regulate their stability (35,36). In turn, GSK3β activity is inhibited by several kinases, including the Akt, Wnt, and MAPK pathways (37). It is known that the prosurvival kinase, Akt, can phosphorylate GSK3β at its N terminus, leading to its inactivation.…”

Section: E2-mediated Gsk3βmentioning

confidence: 99%

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Sareddy

Zhang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3β (GSK3β)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3β, E2 modulates interaction of PELP1 with GSK3β, and PELP1 is a novel substrate for GSK3β. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/ β-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.he steroid hormone, 17β-estradiol (E2), exerts multiple actions in the brain, including regulation of synaptic plasticity, neurogenesis, reproductive behavior, and cognition. E2 has also been implicated to serve as an important neuroprotective factor in a variety of neurodegenerative disorders, including stroke and Alzheimer's disease (1-3). The main source of E2 synthesis in females is the ovary. Circulating E2 levels are known to fluctuate during development and puberty, as well as during the menstrual cycle. After menopause, however, circulating E2 levels decline precipitously (4). Relative to men, women are "protected" against stroke until the years of menopause. However, after menopause, women exhibit a significantly higher disability and fatality rate compared with men (5-7). Intriguingly, the higher risk and poorer outcome of stroke in postmenopausal women parallels the falling E2 levels that occur after menopause (7,8). Furthermore, exogenous administration of E2 significantly reduces the infarct volume in cortex and hippocampus after focal and global cerebral ischemia (GCI) in various animal models, and female animals exhibit reduced neural damage compared with young adult males after brain injury (1, 9-11). Taken as a whole, these studies suggest E2 functions as an important neuroprotective factor. However, the molecular mechanisms by which E2 exerts its neuroprotective effects remain unclear.E2 signaling is thought to be primarily mediated by the classical...

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Section: E2-mediated Gsk3βmentioning

confidence: 99%

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Sareddy

Zhang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Phosphorylation of Mcl-1 (Ser159) by GSK3β may regulate proteasome-dependent degradation [47]. GSK-3β is a ubiquitously expressed serine/threonine protein kinase that is subject to multiple regulatory mechanisms [48,49]. The activity of GSK3β can be reduced by phosphorylation at Ser9 in a PI3K/Akt dependent manner [50,51].…”

Section: Discussionmentioning

confidence: 99%

Isoquercitrin Inhibits Hydrogen Peroxide-Induced Apoptosis of EA.hy926 Cells via the PI3K/Akt/GSK3β Signaling Pathway

Zhu

Wang

et al. 2016

Molecules

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Abstract:Oxidative stress plays a critical role in endothelial injury and the pathogenesis of diverse cardiovascular diseases, including atherosclerosis. Isoquercitrin (quercetin-3-glucoside), a flavonoid distributed widely in plants, exhibits many biological activities, including anti-allergic, anti-viral, anti-inflammatory, and anti-oxidative effects. In the present study, the inhibitory effect of isoquercitrin on H 2 O 2 -induced apoptosis of EA.hy926 cells was evaluated. MTT assays showed that isoquercitrin significantly inhibited H 2 O 2 -induced loss of viability in EA.hy926 cells. Hoechst33342/PI and Annexin V-FITC/PI fluorescent double staining indicated that isoquercitrin inhibited H 2 O 2 -induced apoptosis of EA.hy926 cells. Western blotting demonstrated that isoquercitrin prevented H 2 O 2 -induced increases in cleaved caspase-9 and cleaved caspase-3 expression, while increasing expression of anti-apoptotic protein Mcl-1. Additionally, isoquercitrin significantly increased the expression of p-Akt and p-GSK3β in a dose-dependent manner in EA.hy926 cells. LY294002, a PI3K/Akt inhibitor, inhibited isoquercitrin-induced GSK3β phosphorylation and increase of Mcl-1 expression, which indicated that regulation of isoquercitrin on Mcl-1 expression was likely related to the modulation of Akt activation. These results demonstrated that the anti-apoptotic effect of isoquercitrin on H 2 O 2 -induced EA.hy926 cells was likely associated with the regulation of isoquercitrin on Akt/GSK3β signaling pathway and that isoquercitrin could be used clinically to interfere with the progression of endothelial injury-associated cardiovascular disease.

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“…GSK3β is a central node over which many different signaling pathways converge. Several kinases phosphorylate GSK3β at the same site as AKT, including p90RSK, a direct substrate of ERK1 on the RAS-RAF-MEK-ERK pathway [41]. Furthermore, GSK3β is a key intermediate in the WNT signaling cascade and can be activated independently of the PI3K pathway [42].…”

Section: Discussionmentioning

confidence: 99%

Characterisation of the Phosphatidylinositol 3-Kinase Pathway in Non-Small Cell Lung Cancer Cells Isolated from Pleural Effusions

Puglisi

Stewart²,

Thavasu³

et al. 2016

Oncology

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Objectives: We hypothesised that it was possible to quantify phosphorylation of important nodes in the phosphatidylinositol 3-kinase (PI3K) pathway in cancer cells isolated from pleural effusions of patients with non-small cell lung cancer (NSCLC) and study their correlation to somatic mutations and clinical outcomes. Materials and Methods: Cells were immunomagnetically separated from samples of pleural effusion in patients with NSCLC. p-AKT, p-S6K and p-GSK3β levels were quantified by ELISA; targeted next-generation sequencing was used to characterise mutations in 26 genes. Results: It was possible to quantify phosphoproteins in cells isolated from 38/43 pleural effusions. There was a significant correlation between p-AKT and p-S6K levels [r = 0.85 (95% confidence interval 0.73-0.92), p < 0.0001], but not p-AKT and p-GSK3β levels [r = 0.19 (95% confidence interval -0.16 to 0.5), p = 0.3]. A wide range of mutations was described and p-S6K was higher in samples that harboured at least one mutation compared to those that did not (p = 0.03). On multivariate analysis, p-S6K levels were significantly associated with poor survival (p < 0.01). Conclusion: Our study has shown a correlation between p-AKT levels and p-S6K, but not GSK3β, suggesting differences in regulation of the distal PI3K pathway by AKT. Higher p-S6K levels were associated with adverse survival, making it a critically important target in NSCLC.

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GSK-3 – at the crossroads of cell death and survival

Cited by 156 publications

References 126 publications

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Isoquercitrin Inhibits Hydrogen Peroxide-Induced Apoptosis of EA.hy926 Cells via the PI3K/Akt/GSK3β Signaling Pathway

Characterisation of the Phosphatidylinositol 3-Kinase Pathway in Non-Small Cell Lung Cancer Cells Isolated from Pleural Effusions

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