Chronic over-nutrition and dysregulation of GSK3 in diseases

Liu, Xunxian; Yao, Zemin

doi:10.1186/s12986-016-0108-8

Cited by 29 publications

(28 citation statements)

References 225 publications

(316 reference statements)

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“…Glycogen synthase kinase 3 (GSK3) is a family of serine/threonine kinases comprising GSK3α and GSK3β which was originally identified as a key controller of metabolism via its inhibitory phosphorylation of glycogen synthase [1]. More recently, GSK3 has been shown to control a broad range of cellular functions through phosphorylation of many target proteins [2]. These functions include cell-cycle progression, energy homeostasis and inflammation [2].…”

Section: Introductionmentioning

confidence: 99%

CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor

Phyu

Tseng

Smith

2018

Magn Reson Mater Phy

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PurposeGlycogen synthase kinase 3 (GSK3) is a key controlling element of many cellular processes including cell-cycle progression and recent studies suggest that GSK3 is a potential anticancer target. Changes in glucose metabolism associated with GSK3 inhibition may impact on lipid synthesis, whilst lipid metabolites can act as molecular response markers.MethodsHere, SKBr3 breast and HCT8 colorectal cancer cells were treated with the GSK3 inhibitor SB216763, and [14C (U)] glucose and [3H] choline incorporation into lipids was determined. Cell extracts from treated cells were subject to 31P NMR spectroscopy.ResultsSB216763 treatment decreased choline incorporation into lipids and caused an accumulation of CDP-choline which was accompanied by decreased conversion of glucose into lipid components.ConclusionSB216763 profoundly inhibits phospholipid synthesis in cancer cells which demonstrate accumulation of CDP-choline detectable by 31P NMR spectroscopy. Metabolic changes in lipid metabolism present potential response markers to drugs targeting GSK3.

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Section: Introductionmentioning

confidence: 99%

CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor

Phyu

Tseng

Smith

2018

Magn Reson Mater Phy

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“…GSK is constitutively active and is inhibited either by Ser-9 phosphorylation or protein-binding sequestration (43,44). It has been shown that GSK3B activity can be regulated by scaffolds like AKAP220 (45).…”

Section: Discussionmentioning

confidence: 99%

Scaffolding protein IQ motif containing GTPase activating protein 2 (IQGAP2) regulates glycogen metabolism

Wendt

et al. 2020

Preprint

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Running title: IQGAP2 alters GSK3 activityKeywords: scaffold protein, glycogen synthase kinase 3 (GSK-3), beta-catenin (β-catenin), liver, carbohydrate and lipid metabolism AbstractThe liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes of fats, proteins, and carbohydrates. The IQ motif containing GTPase activating protein 2 (IQGAP2) is a member of the IQGAP family. Of the three homologous isoforms, the IQGAP2 scaffolding protein is predominantly found in the liver. To characterize its role in regulating metabolism, Iqgap2 -/female and male mice, and their WT controls, were fed ad libitum or fasted for 24 hours. Hepatic gene expression, protein levels, and the metabolic response were compared between WT and Iqgap2 -/mice, using RT-qPCR, western blot analysis, and histological stains. We found that loss of IQGAP2 alters the phosphorylation of active glycogen synthase kinase 3 (GSK3) expression, a known regulator of glycogen synthesis and lipogenesis. Consistent with this result, Iqgap2 -/female mice displayed depletion of periportal glycogen even in the fed state. We also observed the blunted expression of genes involved in glycogenesis and lipogenesis when IQGAP2 was deleted. Since GSK3 is known to regulate the activity of β-catenin, we examined and found it to be reduced in Iqgap2 -/mice. Our findings demonstrate that IQGAP2 plays an important role in regulating glycogen synthesis.

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“…On the basis of recent experimental observation that elevated IL-17RC expression was present in peripheral blood samples of AMD patients [ 6 ] and that overexpression of IL-17RC in transfected RPE or monocytes was associated with uncontrolled GSK3 activation [ 8 ] , we postulated that the etiology of AMD might be related to overstimulation-induced-insensitivity of the PI3K/Akt/GSK3 pathway and uncontrolled (or released) GSK3 activity [ 15 ] . To test this hypothesis, we examined the phosphorylation status of PI3K, Akt, and GSK3, as well as that of GSK3 substrates in PBMC of AMD patients.…”

Section: Discussionmentioning

confidence: 99%

Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Liu

Yao

2017

J Biomed Res

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Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C (IL-17RC), a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration (AMD), was associated with altered activation of phosphatidylinositide 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 (GSK3). We wondered whether or not altered PI3K, Akt, and GSK3 activities could be detected in peripheral blood mononuclear cells (PBMC) obtained from AMD patients. In the patients' PBMC, absent or reduced serine-phosphorylation of GSK3α or GSK3β was observed, which was accompanied with increased phosphorylation of GSK3 substrates (e.g. CCAAT enhancer binding protein α, insulin receptor substrate 1, and TAU), indicative of enhanced GSK3 activation. In addition, decreased protein mass of PI3K85α and tyrosine-phosphorylation of PI3K50α was present in PBMC of the AMD patients, suggesting impaired PI3K activation. Moreover, abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients. These data demonstrate that despite the presence of high levels of IL-17RC, Wnt-3a and vascular endothelial growth factor, the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients. Thus, measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD.

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Chronic over-nutrition and dysregulation of GSK3 in diseases

Cited by 29 publications

References 225 publications

CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor

CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor

Scaffolding protein IQ motif containing GTPase activating protein 2 (IQGAP2) regulates glycogen metabolism

Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

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