p(HGNC:GSK3B, pmod(Ph, Ser, 9))

Entity

Name

GSK3B

Namespace

hgnc

Namespace Version

20180906

Namespace URL

https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

We found a significant increase in brain AKT Ser473 phosphorylation (T-test, P<0.001) and GSK3β Ser9 phosphorylation (T-test, P<0.001) in Tg Tau P301S mice treated with anatabine. Figure 11. DOI:10.4172/2168-975X.1000126

GSK3β is inactivated upon phosphorylation of Ser9 by protein kinase B (AKT) [41] whereas AKT phosphorylation at Ser473 results in AKT activation [42]. DOI:10.4172/2168-975X.1000126

The treatment of cortical neurons with compound C, a selective AMPK inhibitor (33), reduced the inhibitory phosphorylation of GSK3b at Ser9 and markedly increased tau phosphorylation at Ser396/404 PubMed:22419736

Conversely, treatment with AICAR (5-aminoimidazole-4- carboxamide ribonucleoside), an AMPK activator (34), increased the inhibitory phosphorylation of GSK3b and reduced tau phosphorylation at Ser396/404 in SH-SY5Y cells and cortical neurons PubMed:22419736

In addition, we found that transient expression of AK1 (but not AK1 R132A mutant) markedly reduced the inhibitory phosphorylation of GSK3b at Ser9 (Fig. 4D and Supplemen- tary Material, S6A), indicating that AK1 may regulate GSK3b activity. PubMed:22419736

DMF increased the phosphorylation levels of GSK-3βSer9 in both genotypes, indicating that this effect is upstream of NRF2 as shown in Fig. 3A. PubMed:29121589

Western blot analysis of different experimental groups, primary hippocampal neuron cells concurrent treatment with different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA for 24 h, also showed that glucose–BSA inhibited the phosphorylation of GSK-3b in a concentration-dependent manner (Fig. 4(a)). And 100 nM GLP-1 or Ex-4 can up-regulate phosphorylation of GSK-3b at Ser9, which was decreased by treatment with glucose–BSA (Fig. 4(b, c)). PubMed:24183963

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10]. PubMed:29121589

Western blot analysis of different experimental groups, primary hippocampal neuron cells concurrent treatment with different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA for 24 h, also showed that glucose–BSA inhibited the phosphorylation of GSK-3b in a concentration-dependent manner (Fig. 4(a)). And 100 nM GLP-1 or Ex-4 can up-regulate phosphorylation of GSK-3b at Ser9, which was decreased by treatment with glucose–BSA (Fig. 4(b, c)). PubMed:24183963

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

These findings suggest a scenario in which MC-LR-mediated demethylation of PP2Ac is associated with GSK-3β phosphorylation at Ser9 and contributes to dissociation of Bα from PP2Ac, which would result in Bα degradation and disruption of PP2A/Bα-tau interactions, thus promoting tau hyperphosphorylation and paired helical filaments-tau accumulation and, consequently, axonal degeneration and cell death. PubMed:29228318

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9,Aand B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948

We found that KT5270 effectively suppressed GSK3β phosphorylation at Ser-9 induced by BAY61-3606 (Fig. 10B) suggesting that this event is mediated by an activation of PKA. PubMed:25331948

GSK3β phosphorylation at Ser-9 has been shown to be mediated by PKA and AKT (protein kinase B) (57, 58). PubMed:25331948

GSK3β phosphorylation at Ser-9 has been shown to be mediated by PKA and AKT (protein kinase B) (57, 58). PubMed:25331948

We found that KT5270 effectively suppressed GSK3β phosphorylation at Ser-9 induced by BAY61-3606 (Fig. 10B) suggesting that this event is mediated by an activation of PKA. PubMed:25331948

GSK3β is inactivated upon phosphorylation of Ser9 by protein kinase B (AKT) [41] whereas AKT phosphorylation at Ser473 results in AKT activation [42]. DOI:10.4172/2168-975X.1000126

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9, A and B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948

Western blot analysis of different experimental groups, primary hippocampal neuron cells concurrent treatment with different concentrations (0, 50, 100, 200 lg/ml) of glucose–BSA for 24 h, also showed that glucose–BSA inhibited the phosphorylation of GSK-3b in a concentration-dependent manner (Fig. 4(a)). And 100 nM GLP-1 or Ex-4 can up-regulate phosphorylation of GSK-3b at Ser9, which was decreased by treatment with glucose–BSA (Fig. 4(b, c)). PubMed:24183963

The second mechanism is related to GSK-3, which phosphorylates NRF2 creating a recognition site for β-Transducin Repeat Containing E3 Ubiquitin Protein Ligase (β-TrCP). β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [8]. Since GSK-3β is inhibited by phosphorylation at Ser9 by Ser/Thr protein kinases such as AKT, it has been suggested that NRF2 might be up-regulated through activation of AKT and permanent inactivation of GSK-3 [9], [10]. PubMed:29121589

This study aimed to investigate the protective effects and mechanism of the novel HDAC6 inhibitor, MPT0G211, using an AD model. Our results indicated that MPT0G211 significantly reduced tau phosphorylation and aggregation, the processes highly correlated with the formation of NFTs. This HDAC6 inhibitory activity resulted in an increase in acetylated Hsp90, which decreased Hsp90 and HDAC6 binding, causing ubiquitination of phosphorylated tau proteins. In addition, a significant increase of phospho-glycogen synthase kinase-3β (phospho-GSK3β) on Ser9 (the inactive form) through Akt phosphorylation was associated with the inhibition of phospho-tau Ser396 in response to MPT0G211 treatment. PubMed:29844403

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT PubMed:21734277

We observed that pharmacological inhibition of Syk with BAY61-3606 stimulates Ser-9 phosphorylation of GSK3β in SH-SY5Y cells (Fig. 9,Aand B) suggesting that blocking Syk activity results in GSK3β inhibition. PubMed:25331948