IndraLab
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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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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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"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 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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"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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"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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"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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"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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"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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"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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"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."
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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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"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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"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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"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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"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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"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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"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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"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."