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AKT phosphorylates GSK3. 882 / 1008
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"In fact, the presence of conserved Ser512 four residues downstream of Ser508 conforms to a GSK3β phosphorylation consensus site (35), that if verified, would strongly link the function of CEACAM1 to insulin-mediated glucose and lipid regulation, since the action of insulin on its receptor results in the phosphorylation of Akt, which phosphorylates GSK3β, ultimately inhibiting glycogen synthase (35) and affecting both glucose and lipid regulation (36)."
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"By exploring downstream targets of IGF2R in BWS LCLs, our analysis reveals a downregulation in the AKT/mTOR signaling axis, characterized by reduced phosphorylation of AKT and S6.PI3K/AKT signaling has several downstream targets, among which GSK-3, when phosphorylated on Ser 9 residue by AKT, is inhibited in its activity."
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"Taking into account it’s circadian rhythmicity, if GSK3β is active when TLR4s are initially activated, in a healthy person there should be an immediate release of pro-inflammatory cytokines, however LPS stimulation of TLR4s should also activate the PI3K/Akt pathway, which would normally result in phosphorylation and inactivation of GSK3β."
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"DCT induced PI3K and Akt activation resulted in downstream phosphorylation of GSK-3 (Ser (21/9)) and BAD (Ser (136)), and nuclear translocation (activation) of NF-kappaB, thereby confirming that DCT induced activation of PI3K and Akt signaling regulates both proproliferative and prosurvival signals."
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"Ischemic preconditioning-induced, Akt-dependent phosphorylation and inactivation of its downstream target glycogen synthase kinase-3 (GSK-3) were initially speculated to confer cardioprotection because both preconditioning and pretreatment with GSK-3 inhibitors reduced infarct size to a similar extent [ xref ]."
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"PGE stimulation of EP2 and EP4 activated the transcription factors T-cell factor (Tcf) and lymphocyte enhancer factor (Lef) signaling via PKA- and phosphatidylinositol 3-kinase/proteinkinase B (PI3K/Akt)-dependent phosphorylation of glycogen synthase kinase 3 (GSK3), thus promoting translocation of the transcription cofactor β-catenin into the nucleus where interaction with Tcf and Lef modulated gene expression, e.g., of COX2 [52,53]."
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"Akt can also phosphorylate Gsk3, releasing its inhibition on mTOR; as such, co-administering Gsk inhibitors with ketamine potentiates its effects and lowers the required dose of ketamine (Inoki et al., 2006; Beurel et al., 2011; Kitagishi et al., 2012; Liu et al., 2013; Dossat et al., 2018)."
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"The phosphorylation and activity of Akt, a major downstream effector of PI 3-kinase, as well as Akt-dependent phosphorylation of glycogen synthase kinase-3 and p70S6 kinase were not affected by the lack of IRS-2; however, there was a decrease in insulin stimulation of Akt associated with the plasma membrane."
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"Akt can phosphorylate and inactivate GSK3 to prevent its functions in maintaining B cell quiescence, xref and regulate mTOR via phosphorylation and inactivation of mTOR inhibitors PRAS40 and TSC2. xref , xref Akt1/2-deficient B cells show impaired cMyc expression and mTOR activity, reduced glucose uptake and cell growth, and mount poor GC and PC responses. xref We found that uncoupling of TAPP1/2 from the PI3K product PI(3,4)P2 leads to hyperactivation of Akt, increased glucose uptake, and B cell hyperactivation in vitro and in vivo. xref We and others have shown that PI3K can regulate the expression of glucose transporter GLUT1, xref , xref , xref , xref , xref suggesting that one mechanism by which PI3K promotes glucose utilization is by ensuring sufficient glucose transport capacity."
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"Since the dominant negative ILK-KD can inhibit PKB phosphorylation and activity in PC3 cells (Persad et al. 2000), and since PKB can phosphorylate and inactivate GSK-3 (Cross et al. 1995), it was necessary to evaluate the PKB dependence of PTEN- and ILK mediated regulation of GSK-3 and subsequently beta-catenin."
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"AKT-mediated GSK3 inhibition is determined by AKT phosphorylation on GSK3 NH2-terminus, forming an intramolecular pseudo-substrate that obstructs the phosphate-binding pocket, and consequently, suppresses substrate availability to GSK3 [ xref ] (Fig. xref a) (Supplementary information xref )."
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"Based on the notion that ERK mediated phosphorylation of MYC Ser-62 results in stabilization of the MYC protein, and activated AKT phosphorylates and inactivates GSK3, thereby inhibiting the phosphorylation of MYC at Thr-58 that promotes MYC degradation, it is possible that both the ERK and AKT pathways may be involved in the regulation of MYC protein stability in bladder cancer with aberrant FGFR3 activation (Fig. 3) [116, 125, 126, 128]."
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"Conversely, D2-receptor antagonists such as haloperidol, raclopride, and atypical antipsychotics such as clozapine, risperidone, olanzapine, quetiapine, and ziprasidone (their common profile is dual antagonism of 5HT2A receptors and D2-receptors [233,234]) all induce inhibition of GSK3, owing to the inhibitory phosphorylation of GSK3 by PKB [235,236]."
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"Several studies have shown that AKT activation can induce the phosphorylation of downstream GSK3β, prevent the degradation of β-catenin by the APC-axin-GSK3β complex and promote its aggregation, thereby activating the Wnt/β-catenin signaling pathway, stimulating the expression of osteogenic factors, and promoting the osteogenic differentiation of mesenchymal stem cells [52,53]."
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"The in vitro data complemented the in vivo data by showing that UT attenuated the inhibitory effects of FFAs on Akt phosphorylation at Ser 473 and Thr 308 and insulin stimulated glycogen synthesis; an essential downstream function that results from the phosphorylation and inactivation of GSK-3 by Akt."
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"For example, this may take the form of additional components to allow for the formation of active NCoR/SMRT complexes.Alternatively, pathologic HDAC3 activity in RGCs may require secondary modifications such as phosphorylation by glycogen synthetase kinase 3β (GSK3β).16 Regulation of GSK3β is mediated in many cells by the activity of the AKT/PI3 Kinase complex.108 109 AKT phosphorylates GSK3β rendering it inactive, but inhibition (or loss of activity) of AKT results in accumulation of dephosphorylated GSK3β and its activation."
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"mTOR and then signals to the translation machinery via the activation of S6K, which controls the ribosomal protein S6, and the inhibition of 4EBP1, which hinders translation initiation by sequestering EIF4E. xref AKT also phosphorylates and inhibits GSK3, thus relieving GSK3‐dependent inhibition of EIF2B. xref "
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"We speculate that upon D2R activation and recruitment of the complex, GSK3β will be dephosphorylated by PP2A and less phosphorylated by Akt (which is dephosphorylated and inhibited by PP2A), resulting in greater changes in pGSK3β levels that can be better detected by immunostaining."
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"Remarkably, the activation of these signalling pathways was not fully compromised in EIF4A3‐silenced cells in that other ligand such as insulin (100 nM) induced a similar or even higher level of phosphorylation of GSK3β, ERK and AKT in scramble‐ and EIF4A3‐silenced cells (Figure S5A,B), suggesting a selective role of EIF4A3 in the modulation of FGF19/FGFR4 pathway.3."
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"Since the dominant negative ILK-KD can inhibit PKB phosphorylation and activity in PC3 cells ( xref ), and since PKB can phosphorylate and inactivate GSK-3 ( xref ), it was necessary to evaluate the PKB dependence of PTEN- and ILK-mediated regulation of GSK-3 and subsequently β-catenin."
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"Mechanistically, although the suppression of Akt phosphorylation and induction of GSK3β-Ser9 inactivation by TA3 was blocked by pretreatment with insulin, the inhibitory effect of mSREBP-1, FASN, and ACC expression by TA3 was maintained, even with pretreatment with insulin as much as when treated with TA3 alone."
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"Activated Akt directly phosphorylates and inhibits GSK3 ( xref ), which is a key regulator of Myc protein stability ( xref ), thus we wanted to test whether Akt pathway activation might substitute for MYC transgene activation by inducing the transcriptional activity of endogenous Myc."
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"In fasting–refeeding studies, Akt2 −/− mice had impaired hepatic glycogen synthesis, which demonstrates the necessity of AKT for insulin-dependent stimulation of glycogen synthesis; however, Gsk3α Ser21Ala / Gsk3β Ser9Ala mice displayed normal hepatic glycogen metabolism, suggesting that inhibitory phosphorylation of GSK3 by AKT is unnecessary for glycogen synthesis xref ."
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"In fasting refeeding studies, Akt2 -/- mice had impaired hepatic glycogen synthesis, which demonstrates the necessity of AKT for insulin dependent stimulation of glycogen synthesis; however, Gsk3alpha Ser21Ala / Gsk3beta Ser9Ala mice displayed normal hepatic glycogen metabolism, suggesting that inhibitory phosphorylation of GSK3 by AKT is unnecessary for glycogen synthesis 156."
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"The activity of Akt in mitochondria is rapidly and strongly regulated by intracellular signalling activities and stimulates phosphorylation of GSK3β in mitochondria [42], then leading to potentiating dephosphorylation of pyruvate dehydrogenase (PDH) [43] and enabling its activation to maintain the enhanced mitochondrial oxidative capacity [44]."
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"Akt also phosphorylates and inactivates GSK-3 (Ser9), thus suppressing its inhibition of downstream substrate Bcl-2, a pro-survival factor that inhibits caspase-9 cascade activation in the mitochondrial apoptosis pathway, thus suppressing apoptosis and promoting cell survival [ xref – xref ]."
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"Activation of β-catenin by PGE2 is not mediated by a canonical cAMP/ PKA pathway, but requires a different dual mechanism that involves: (i) binding of activated Gαs to axin (through the RGS domain) leading to a disruption of the axin-GSK3 complex, and (ii) simultaneous activation of Gβγ (presumably released from GTP-Gαs) resulting in a canonical Gβγ-mediated activation of PI3 kinase and AKT-dependent phosphorylation and inactivation of GSK-3 [ xref ]."
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"In healthy brains, insulin regulates various functions, including memory and synaptic plasticity [186], with the PI3K/Akt/GSK3β pathway being central to these processes, where Akt, a serine/threonine kinase, phosphorylates and inactivates GSK3β, promoting glycogen synthesis and supporting cellular health [187]."
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"Activated Akt can directly phosphorylate glycogen synthase kinase-3 ( xref ) and 6-phosphofructo 2-kinase ( xref ) that are important for protein synthase and insulin signaling; it also phosphorylates the B-cell CLL/lymphoma (Bcl-2)-associated death promoter (BAD) that interacts with the Bcl family member BclxL, thus preventing apoptosis of some cells ( xref )."
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"The following cellular processes were observed in vitro in a manner dependent on insulin, time of incubation, and exogenous ATP: 1) autophosphorylation and activation of the insulin receptor; 2) tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1); 3) association of tyrosine-phosphorylated IRS-1 with phosphoinositide 3-kinase; 4) activation of the kinase Akt via its phosphorylation on Thr-308 and Ser-473; and 5) phosphorylation of glycogen synthase kinase-3 by activated Akt."
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"Western blotting revealed increases in phosphorylated Akt (pAkt) and phosphorylated glycogen synthase kinase-3 (pGSK-3) following acute and repeated treatment of LY379268 (mGlu(2/3) agonist), whereas increases in dishevelled-2 (Dvl-2), dishevelled-3 (Dvl-3), GSK-3 and β-catenin were only observed following repeated treatment."
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"AKT phosphorylates GSK3β to inhibit its activity (Cross et al., 1995), which could lead to changes in mitochondrial transport (Embi et al., 1980; Cohen and Frame, 2001), glycogen synthase (Embi et al., 1980; Cohen and Frame, 2001), and mitochondrial function (Detmer and Chan, 2007; Amiri and Hollenbeck, 2008; Liu et al., 2009; Twig et al., 2010)."
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"Activated PI3K converts phosphorylation of phosphatidylinositol biphosphate (PIP2) into phosphatidylinositol 3-phosphate (PIP3) which promotes activation of protein kinase B (PKB/Akt), and then PKB/Akt phosphorylates its downstream functional molecule including mTOR, IκB, and GSK3β (14–16)."
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"Furthermore, PTEN-deficient GBM cells activate the PI3K/AKT pathway, which suppresses interferon regulatory factor 1 (IRF1) degradation by phosphorylating glycogen synthase kinase 3 beta (GSK3β) into its inactive form, with higher levels of IRF1, inducing Gal-9 transcription (Figure 2)."
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"AKT is a key kinase in the insulin signaling pathway and serves as a pivotal regulator in the maintenance of glucose homeostasis.5 AKT can phosphorylate and inactivate GSK3β, therefore promoting glycogen synthesis.5 AKT phosphorylation is decreased in the state of insulin resistance, leading to the activation of GSK3β and a decrease in glycogen synthesis."
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"AKT phosphorylates and inhibits GSK-3 320 and Wnt causes GSK-3 dislocation from the destruction complex. xref GSK-3β is rich in the brain and is involved in neurogenesis, neurotransmission, and regulation of synaptic plasticity. xref However, it has also been implicated in the formation of neurofibrillary tangles in Alzheimer's disease. xref GSK-3β can be inhibited by lithium, which is used as a mood stabilizer for treating bipolar disorder. xref GSK-3β also enhances apoptosis via up-regulation of p53. xref GSK-3 can also modulate inflammation downstream of TLR signaling; activation of GSK-3 leads to the production of the pro-inflammatory cytokines IL-6, IL-1B, and IFNy, while inhibition of GSK-3 leads to the production of anti-inflammatory IL-10. xref "
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"Dopamine receptor activation may have multiple effects on GSK3 function, which depend upon the receptor involved and whether they act through D 2 receptor mediated beta-arrestin2 and protein phosphatase 2A (PP2A) recruitment (increased Akt phosphorylation and release of GSK3 from Akt regulation) or through D 1 and/or D 2 -mediated tyrosine kinase transactivation (enhanced Akt action and consequent GSK3 phosphorylation and inactivation) [XREF_BIBR]."
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"More recent findings showed that disruption of GSK-3 phosphorylation by AKT decreases anxiety and reduces proneness to depression in mice 45 and intracellular signal transduction system as AKT and GSK-3beta pathway have been found to be altered in the brain of depressive patients 46."
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"Surprisingly, we found that the BCR induced phosphorylation of GSK-3 on its negative regulatory sites, as well as the subsequent up-regulation of beta-catenin, was not mediated by Akt but by the phospholipase C dependent activation of protein kinase C. Thus, the BCR regulates beta-catenin levels via a phospholipase C/protein kinase C/GSK -3 pathway."
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"Recent phosphoproteome analysis of RVFV-infected cells showed that infection led to the dephosphorylation of the Akt-phosphorylated sites of FOXO1 and GSK3β.125 The authors also observed a dephosphorylation of IRS1, an insulin-receptor adaptor that can facilitate PI3K/Akt activation."
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"After binding to its receptor tropomyosin receptor kinase B (TrkB), BDNF activates phosphatidylinositol 3-kinase (PI3K), phosphorylating and activating serine/threonine kinase Akt, a major cell survival factor that in turn phosphorylates and inactivates GSK-3, an evolutionally conserved kinase comprising α and β isoforms (Kaidanovich-Beilin and Woodgett, 2011; Leeds et al., 2014)."
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"Since Akt kinase phosphorylates GSK3 in a highly conserved N-terminal regulatory site inactivating GSK3 [ xref ] and it is activated by DHA [ xref ], reduced binding of C/EBP to DNA by omega-3 PUFA in IL-1β-stimulated astrocytes may be caused by inhibition of GSK-3 activity [ xref ]."
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"Sustained lenvatinib treatment also induces the phosphorylation of c-Met, which in turn activates its downstream factors, Akt and ERK.18 Akt activation can increase the phosphorylation of GSK3β, thus inhibiting its function,15 resulting in suppressed cleavage of apoptotic proteins caspase-9 and caspase-3."
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"For example, activated AKT can directly phosphorylate GSK3 to inhibit its activity XREF_BIBR; this leads to the nuclear translocation of beta-catenin to induce the expression of several cell cycle related genes such as CCND1 (symbol of Cyclin D1), which then promotes cell cycle progression via regulation of Rb phosphorylation."
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"PI3K can activate its downstream molecule Akt, which further phosphorylates fox OS, GSK-3, Bad, mTOR, and other proteins to cause a cascade reaction that plays a key role in the accumulation of extracellular matrix, mesangial cell proliferation, epithelial-mesenchymal transformation, and other aspects of diabetic nephropathy [XREF_BIBR, XREF_BIBR]."
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"In addition to direct inhibition of GSK3beta activity, Li has also been shown to indirectly inhibit GSK3beta activity via mechanisms such as disruption of beta-arrestin-2 signaling complex with PP2A that consequently activates Akt phosphorylation and inhibition of GSK3 [XREF_BIBR]."
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"For example, activated AKT can directly phosphorylate GSK3 to inhibit its activity xref ; this leads to the nuclear translocation of β-catenin to induce the expression of several cell cycle-related genes such as CCND1 (symbol of Cyclin D1), which then promotes cell cycle progression via regulation of Rb phosphorylation."
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"However, neurons from the GSK3α-S21A/GSK3β-S9A double knockin mice, in which GSK3 cannot be phosphorylated by AKT, show no defect in neuronal polarization (Gartner et al., xref ), arguing against the idea that PI3K controls neuronal polarization via AKT-mediated GSK3 inactivation."
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"DRG2 depletion extends the expression of EGFR on Rab5-containing endosomes and increases the activity of Akt and inhibitory phosphorylation of GSK3β, thus reducing the phosphorylation of Tau, which leads to an enhanced interaction between Tau and MT and hyperstabilization of MTs [19]."
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"XREF_BIBR, XREF_BIBR There is evidence that glucocorticoid treatment reduces mammary tight junction permeability in both bovine XREF_BIBR, XREF_BIBR and rat XREF_BIBR, XREF_BIBR in vitro models, via downregulation of the small GTPase RhoA XREF_BIBR and phosphorylation of GSK3 by Akt."
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"More recent findings showed that disruption of GSK-3 phosphorylation by AKT decreases anxiety and reduces proneness to depression in mice xref and intracellular signal transduction system as AKT/GSK-3β pathway have been found to be altered in the brain of depressive patients xref ."
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"Increased phosphorylation of AKT (increased AKT activities) causes phosphorylation of GSK3β (suppression of GSK3β activities) at the serine 9 residue while reduced phosphorylation of AKT (reduced AKT activities) decreases levels of phosphorylation of GSK3β (increased GSK3β activities) (Beurel et al., 2010)."
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"An important observation for understanding the dominant role of NRF2 in driving aggressive cell proliferation is that nuclear accumulation of NRF2 is greatly enhanced in the presence of proliferative signals. xref , xref , xref Whereas NRF2 is trapped by the CUL3‐KEAP1 complex in the cytoplasm and ubiquitinated for degradation, NRF2 is also ubiquitinated by the CUL1‐βTrCP complex after being phosphorylated by GSK3. xref , xref As GSK3 is phosphorylated by AKT and inactivated, CUL1‐βTrCP complex‐mediated degradation of NRF2 is inhibited in proliferating cells in which the PI3K‐AKT pathway is active."
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"PKB also phosphorylates and inactivates GSK3 ( xref ), an enzyme initially identified as a regulator of glycogen metabolism but which also has broader functions: interactions between GSK3 and β-catenin ( xref ) regulate activity of the T cell factor–lymphoid enhancer factor (Tcf-Lef)."
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"Conversely, D2-receptor antagonists such as haloperidol, raclopride, and atypical antipsychotics such as clozapine, risperidone, olanzapine, quetiapine, and ziprasidone (their common profile is dual antagonism of 5HT2A receptors and D2-receptors [ xref , xref ]) all induce inhibition of GSK3, owing to the inhibitory phosphorylation of GSK3 by PKB [ xref , xref ]."
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"Akt can phosphorylate and inactivate GSK3 to prevent its functions in maintaining B cell quiescence,5 and regulate mTOR via phosphorylation and inactivation of mTOR inhibitors PRAS40 and TSC2.26 27 Akt1/2-deficient B cells show impaired cMyc expression and mTOR activity, reduced glucose uptake and cell growth, and mount poor GC and PC responses."
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"Although activation of cardiac phosphoinositide 3-kinase (PI3K) by growth factors such as insulin is known to stimulate the activity of the kinase Akt, which in turn phosphorylates and inhibits GSK3 activity, recent investigation have suggested that cytokine- stimulated phosphorylation of GSK3 is primarily dependent on PKC signaling rather than PKB signaling [XREF_BIBR]."
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"In addition, AKT phosphorylates and inactivates GSK-3 (glycogen synthase kinase 3), which leads to increased glycogen synthesis, and also prevents phosphorylation and degradation of cyclin D1 ( xref ), a proto-oncogene whose amplification and protein overexpression are often exhibited in tumor cells ( xref )."
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"These Statements are typically ones that represent a canonical (i.e., often described) mechanism (e.g., the mechanism by which members of the AKT protein family phosphorylate GSK3 proteins) at a high level of detail and subsume multiple variants of the same mechanism described at a lower level of detail."
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"Luteolin and carnosic acid were found to inhibit the ejection of Nrf2 as follows: luteolin and carnosic acid both activate PI3K [89, 97] which not only phosphorylates Nrf2 to facilitate its translocation to the nucleus but which also activates Akt; Akt phosphorylates GSK3β, inactivating it, which prevents it from activating cytosolic Fyn; the inactive Fyn remains in the cytosol and cannot enter the nucleus to contribute to the expulsion of Nrf2, meaning that active Nrf2 will have a longer duration in the nucleus, increasing its efficiency."
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"The aims of this study were to determine the effects of four weeks of intermittent exposure to a moderate hypoxia environment (15% oxygen), and compare with the effects of exercise in normoxia or hypoxia, on glucose homeostasis, insulin sensitivity, GLUT4 translocation, insulin receptor phosphorylation, Akt-dependent GSK3 phosphorylation and Akt activity in skeletal muscle of obese mice with type 2 diabetes."
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"In these cells, we not only observe a dramatic and specific inhibition of PKB and Akt serine 473 phosphorylation and down-regulation of cyclin D1 expression but also inhibition of GSK-3 phosphorylation on serine 9, further supporting cell-type specific regulation of GSK-3 phosphorylation by the ILK-PKB and Akt pathway."
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"The improved insulin sensitivity in response to the hypoxia interventions (DH and DHE) appeared to be via an up-regulation of the insulin-dependent signalling pathway as indicated by a significant increase of GLUT4 translocation in the muscle ( xref ), accompanied by the lower IR phosphorylation, Akt expression and Akt-dependent GSK3 phosphorylation (Figs xref and xref ), as compared to the DC."
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"Gsk3b knock-in mice, which harbor a mutation in the AKT-dependent Ser9 phosphorylation site of GSK3β, show no difference in Wnt3a-dependent activation of β-catenin or Wnt gene transcription [84], revealing that AKT phosphorylation of GSK3β does not significantly contribute to Wnt/β-catenin signaling.There is growing evidence that PI3K/AKT signaling regulates Wnt/β-catenin signaling independently of GSK3β (Figure 2)."
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"This may indicate that enriched environmental conditions reduce MSNs output by reducing GSK3β activity at the circuit level, thus inhibiting maladaptive behavior.Similar results were found in GSK3-KI animals: in the SK3α21A/21A/β/9A/9A knock-in mouse, the lack of GSK3 inhibitory phosphorylation by PKB/Akt kinase results in constitutively high GSK3 activity."
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"AKT is a key protein kinase downstream of the insulin receptor [XREF_BIBR] and its activation plays a key role in suppressing hepatic gluconeogenesis [XREF_BIBR, XREF_BIBR], since GSK-3, which phosphorylate glycogen synthetase (GS) is inhibiting, is phosphorylated by AKT, and this phosphorilation inactivates GSK-3 kinase activity, suppressing hepatic gluconeogenesis resulting in enhanced glycogen deposition [XREF_BIBR]."
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"Moreover, expression of nonphosphorylatable active GSK-3 beta mutant GSK-3 beta-A9 suppressed recycling of alpha 5 beta 1 and alpha v beta 3 and reduced cell spreading on ligands for these integrins, indicating that PKB and Akt promotes integrin recycling by phosphorylating and inactivating GSK-3."
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"Moreover, expression of nonphosphorylatable active GSK-3 beta mutant GSK-3 beta-A9 suppressed recycling of alpha 5 beta 1 and alpha v beta 3 and reduced cell spreading on ligands for these integrins, indicating that PKB and Akt promotes integrin recycling by phosphorylating and inactivating GSK-3."
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"Mammary epithelial tight junctions are altered by several hormones including glucocorticoids, xref prolactin, xref serotonin xref and progesterone, and it is the sharp fall in the latter at parturition that allows tight junction closure to provide a leak-proof duct and restore trans-epithelial resistance, thus facilitating lactation. xref Glucocorticoids such as cortisol are raised throughout pregnancy, and decline during lactation. xref , xref There is evidence that glucocorticoid treatment reduces mammary tight junction permeability in both bovine xref , xref and rat xref , xref in vitro models, via downregulation of the small GTPase RhoA xref and phosphorylation of GSK3 by Akt. xref Glucocorticoid treatment has been shown to prevent rat mammary involution in vivo. xref An in vivo study on ovariectomized mice showed that although progesterone withdrawal was the primary trigger for mammary epithelial tight junction closure in late pregnancy (as demonstrated by progesterone antagonism), low to moderate levels of both cortisol and either placental lactogen or prolactin were required for this to happen. xref Unlike progesterone and glucocorticoids, prolactin does not appear to prevent involution in mice, xref although several authors report that prolactin maintains mammary epithelial impermeability in late lactation in rabbits, largely indirectly by preventing apoptosis. xref - xref Interestingly, neutrophils are able to pass through these intercellular junctions to reach the lumen if necessary, with complete reconstitution of tight junctions occurring afterwards. xref "
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"As to how pT308 AKT regulates centrosome functions, several studies have reported that AKT could phosphorylate several substrates, including GSK-3 (Buttrick et al., 2008; Buttrick and Wakefield, 2008; Wakefield et al., 2003), TEIF (Telomerase transcriptional element-interacting factor; Zhao et al., 2014), and Inversin (Suizu et al., 2016), to regulate interphase or mitotic centrosomes functions, respectively."
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"Studies have shown that when insulin resistance occurred in the hippocampus, the activity of PI3K/AKT, the main signaling molecule of the insulin signaling pathway, was decreased, which promoted the activation of GSK3β and phosphorylation of tau and promoted the pathological progression of AD [119]."
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"Increased phosphorylation of Akt (increased Akt activities) causes phosphorylation of GSK3β (suppression of GSK3β activities) at the serine 9 residue while reduced phosphorylation of Akt (reduced Akt activities) decreases levels of phosphorylation of GSK3β (increased GSK3β activities)."
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"However, recent studies in mice with a mutant form of GSK3 that cannot be phosphorylated and inhibited by Akt, still induce glycogen synthesis in response to insulin, indicating that Akt can suppress glycogenolysis through pathways separate from Akt-dependent GSK3 phosphorylation. xref One such independent pathway involves direct activation of glycogen synthase (GYS2)."
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"Lithium treatment resulting in therapeutic lithium serum levels (0.8–1.5 mM) also increases the inhibitory phosphorylation of GSK3 isoforms by Akt, thus providing an indirect mechanism (Figure 1A) for the inhibition of GSK3 by lithium (Chalecka-Franaszek and Chuang, 1999; Beaulieu et al., 2008)."
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"The GSK3 proteins are involved in regulating metabolic function and are phosphorylated and inhibited by Akt among other kinases such as p70S6K. Once phosphorylated, the kinase activity of GSK3 is inhibited, and their substrates such as glycogen synthase, Ap-1, β - catenin, c-myc, and p53, thereby initiating signaling mechanisms promoting cell survival and growth."
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"Further, stabilization of β-catenin protein appears to be due to both cell-extrinsic mechanism seen as increased p-LPR6 (S1490) suggesting Wnt stimulation, and cell-intrinsic mechanism seen as decreased GSK3β activity which was phosphorylated and inhibited by compensatory elevation of AKT activity in the Raptor ∆HC mice."