Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The second messenger cAMP mediates its intracellular effects in spermatozoa through cAMP-dependent kinase (PKA, formally known as PRKACA). The intracellular organization of PKA in spermatozoa is controlled through its association with A-kinase-anchoring proteins (AKAPs). AKAP4 (A kinase [PRKA] anchor protein 4; also called fibrous sheath component 1 or AKAP 82) is sperm specific and the major fibrous sheath protein of the principal piece of the sperm flagellum. Presumably, AKAP4 recruits PKA to the fibrous sheath and facilitates local phosphorylation to regulate flagellar function. It is also proposed to act as a scaffolding protein for signaling proteins and proteins involved in metabolism. Akap4 gene knockout mice are infertile due to the lack of sperm motility. The fibrous sheath is disrupted in spermatozoa from mutant mice. In this article, we used Akap4 gene knockout mice to study the effect of fibrous sheath disruption on the presence, subcellular distribution, and/or activity changes of PKA catalytic and regulatory subunits, sperm flagellum proteins PP1gamma2 (protein phosphatase 1, catalytic subunit, gamma isoform, formally known as PPP1CC), GSK-3 (glycogen synthase kinase-3), SP17 (sperm autoantigenic protein 17, formally known as SPA17), and other signaling proteins. There were no changes in the presence and subcellular distribution for PP1gamma2, GSK-3, hsp90 (heat shock protein 1, alpha, formally known as HSPCA), sds22 (protein phosphatase 1, regulatory [inhibitor] subunit 7, formally known as PPP1R7), 14-3-3 protein (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein), and PKB (thymoma viral proto-oncogene, also known as AKT) in mutant mice. However, the subcellular distributions for PKA catalytic subunit and regulatory subunits, PI 3-kinase (phosphatidylinositol 3-kinase), and SP17 were disrupted in mutant mice. Furthermore, there was a significant change in the activity and phosphorylation of PP1gamma2 in mutant compared with wild-type spermatozoa. These studies have identified potentially significant new roles for the fibrous sheath in regulating the activity and function of key signaling enzymes.
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PMID:Changes in intracellular distribution and activity of protein phosphatase PP1gamma2 and its regulating proteins in spermatozoa lacking AKAP4. 1538 10

Integrins are dynamic membrane proteins that mediate adhesion of cells to the extracellular matrix. Integrins initiate signal transduction, alone and cooperatively with growth factor receptors, and regulate many aspects of cell behavior. We report here that alpha5beta1-mediated adhesion of Ntera2 neuronal cells to fibronectin decreased apoptosis in response to serum withdrawal. Adhesion induced phosphorylation of FAK, and strongly increased the AKT phosphorylation induced by growth factors, demonstrating for the first time in neuronal cells that integrin-mediated adhesion and growth factors cooperate to regulate AKT activity. Integrins exist on cells in different activation states, and cell survival on fibronectin was enhanced by the antibody 12G10, that modulates the conformation of beta1 in favor of its active form. The antibody 12G10 specifically delayed loss of phosphorylation of AKT on serine 473, and GSK-3beta on serine 9, induced by serum withdrawal, suggesting that these kinases are critical sensors of integrin activation on neuronal cells.
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PMID:Activation of integrin alpha5beta1 delays apoptosis of Ntera2 neuronal cells. 1573 47

Activation of activator protein-1 (AP-1) and increased expression of cyclooxygenase-2 (COX-2) have been clearly shown to play a functional role in UVB-induced skin tumor promotion. In this study, we examined UVB-induced signal transduction pathways in SKH-1 mouse epidermis leading to increases in COX-2 expression and AP-1 activity. We observed rapid increases in p38 mitogen-activated protein kinase (MAPK) signaling through activation of p38 MAPK and its downstream target, MAPK activated protein kinase-2. UVB also increased phosphatidylinositol 3-kinase (PI3K) signaling as observed through increases in AKT and GSK-3beta phosphorylation. Activation of the p38 MAPK and PI3K pathways results in the phosphorylation of cyclic AMP-responsive element binding protein, which was also observed in UVB-irradiated SKH-1 mice. Topical treatment with SB202190 (a specific inhibitor of p38 MAPK) or LY294002 (a specific inhibitor of PI3K) significantly decreased UVB-induced AP-1 activation by 84% and 68%, respectively, as well as COX-2 expression. Our data show that in mouse epidermis, UVB activation of the p38 MAPK and PI3K pathways leads to AP-1 activation and COX-2 expression.
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PMID:Inhibition of p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase decreases UVB-induced activator protein-1 and cyclooxygenase-2 in a SKH-1 hairless mouse model. 1575 75

The mammalian cell cycle is regulated by the cyclin/cyclin-dependent kinase (CDK) phosphorylation of the retinoblastoma (pRB) family of proteins. Cyclin D1 with its CDK4/6 partners initiates the cell cycle and acts as the link between extracellular signals and the cell cycle machinery. Estradiol-17beta (E2) stimulates uterine epithelial cell proliferation, a process that is completely inhibited by pretreatment with progesterone (P4). Previously, we identified cyclin D1 localization as a key point of regulation in these cells with E2 causing its nuclear accumulation and P4 retaining it in the cytoplasm with the resultant inhibition of pRB phosphorylation. Here we show that E2 stimulates phosphoinositide 3-kinase to activate phosphokinase B/AKT to effect an inhibitory phosphorylation of glycogen synthase kinase (GSK-3beta). This pathway is suppressed by P4. Inhibition of the GSK-3beta activity in P4-treated uteri by the specific inhibitor, LiCl, reversed the nuclear accumulation of cyclin D1 and in doing so, caused pRB phosphorylation and the induction of downstream genes, proliferating cell nuclear antigen and Ki67. Conversely, inhibition of phosphoinositide 3 kinase by LY294002 or Wortmanin reversed the E2-induced GSK-3beta Ser9 inhibitory phosphorylation and blocked nuclear accumulation of cyclin D1. These data show the reciprocal actions of E2 and P4 on the phosphoinositide 3-kinase through to the GSK-3beta pathway that in turn regulates cyclin D1 localization and cell cycle progression. These data reveal a novel signaling pathway that links E2 and P4 action to growth factor-mediated signaling in the uterus.
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PMID:Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase-->AKT-->GSK-3beta-->cyclin D1-->pRB pathway to block uterine epithelial cell proliferation. 1584 46

The beta-catenin pathway plays a critical role in the pathogenesis of certain types of cancers. To gain insight into mechanisms by which altered receptor tyrosine kinases regulate cytoplasmic beta-catenin accumulation, the effect of an oncogenic receptor originated from Nantes (RON) variant on beta-catenin accumulation and the role of beta-catenin in RON-mediated tumorigenic activities were studied. In NIH3T3 cells harboring oncogenic variant RONDelta160, increased beta-catenin accumulation with tyrosine phosphorylation and nuclear translocation was observed. Overexpression of RONDelta160 also resulted in increased expression of beta-catenin target genes c-myc and cyclin D1. By analyzing cellular proteins that regulate beta-catenin stabilities, it was found that RONDelta160 activates the protein disheveled (DVL) and inactivates glycogen synthase kinase-3beta by Ser-9 residue phosphorylation. These effects were channeled by RONDelta160-activated PI 3-kinase-AKT pathways that are sensitive to specific inhibitors, such as wortmannin, but not to other chemical inhibitors. Silencing RONDelta160 expression by specific small interfering RNA blocked not only beta-catenin expression but also c-myc and cyclin D1 expression, suggesting that RON expression is required for the activation of the beta-catenin signaling pathway. Moreover, it was found that knockdown of the beta-catenin gene expression by small interfering RNA techniques reduces significantly the RONDelta160-mediated NIH3T3 cell proliferation, focus-forming activities and anchorage-independent growth. Thus, the oncogenic RON variant regulates beta-catenin stabilities through activation of DVL and inactivation of glycogen synthase kinase-3beta. The activated beta-catenin cascade is one of the pathways involved in tumorigenic activities mediated by the oncogenic RON variant.
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PMID:Mechanisms of cytoplasmic {beta}-catenin accumulation and its involvement in tumorigenic activities mediated by oncogenic splicing variant of the receptor originated from Nantes tyrosine kinase. 1587 78

Second-generation antipsychotic agents (SGAs) are increasingly replacing first-generation antipsychotic agents due to their superior activity against the negative symptoms of schizophrenia, decreased extrapyramidal symptoms and better tolerability. However, some SGAs are associated with adverse metabolic effects as significant weight gain, lipid disorders and diabetes mellitus. The pathogenesis of SGA-induced disturbances of glucose homeostasis is unclear. In vivo studies suggest a direct influence of SGAs on peripheral insulin resistance. To this end, we analyzed whether olanzapine might alter glycogen synthesis and the insulin-signaling cascade in L6 myotubes. Glycogen content was diminished in a dose- and time-dependent manner. Within the insulin-signaling cascade IRS-1 tyrosine phosphorylation was induced several fold by insulin and was diminished by preincubation with olanzapine. IRS-1-associated PI3K activity was stimulated by insulin three-fold in L6 myotubes. Olanzapine inhibited insulin-stimulated IRS-1-associated PI3K activity in a dose-dependent manner. Protein mass of AKT, GSK-3 and GS was unaltered, whereas phosphorylation of AKT and GSK-3 was diminished, and pGS was increased. Finally, we compared olanzapine with amisulpride, an SGA clinically not associated with the induction of diabetes mellitus. Glycogen content was diminished in olanzapine-preincubated L6 cells, whereas this effect was not observed under the amisulpride conditions. We conclude that olanzapine impairs glycogen synthesis via inhibition of the classical insulin-signaling cascade and that this inhibitory effect may lead to the induction of insulin resistance in olanzapine-treated patients.
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PMID:Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. 1655 Feb 12

The PI3-kinase/Akt pathway promotes cell survival in many different cell types including intestinal epithelial cells. Increased AKT activation in polyamine depleted intestinal epithelial cells correlated well with the decrease in TNF-alpha-induced apoptosis. Increased Akt activation and GSK3beta (Ser 9) phosphorylation without significant effect on Bad (Ser136) phosphorylation indicate that Akt-mediated protection is independent of Bad phosphorylation but may depend on GSK3beta. Pretreatment of polyamine-depleted cells with LY294002 increased caspase-9 and caspase-3 activation and decreased basal levels of GSK-3beta phosphorylation. Inhibition of GSK3beta activity using AR-A014418 or lithium chloride or siRNA-mediated downregulation of its expression had no effect on apoptosis. Inhibition of PI3-kinase and over-expression of dominant negative Akt (DN-AKT), significantly increased apoptosis in polyamine depleted cells. DN-Akt expression reversed the protective effect of polyamine depletion on apoptosis. DN-Akt, as well as the PI3-kinase inhibitors, prevented Akt activation and subsequent translocation of NF-kappaB to the nucleus. Constitutively active Akt (CA-AKT) expression increased resistance to TNF-alpha-induced apoptosis. Constitutively active-Akt expression increased nuclear staining of NF-kappaB. Moreover, polyamine depletion of DN-Akt cells prevented basal and TNF-alpha-induced IkappaBalpha phosphorylation. Prevention of NF-kappaB activation in DN-IkappaBalpha-transfected cells increased apoptosis in control cells and restored it in polyamine-depleted cells to control levels. These data indicate that Akt regulates the mitochondrial pathway, preventing activation of caspase-9 and thereby caspase-3 via NF-kappaB and these effects are independent of GSK-3beta activity.
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PMID:Decreased apoptosis in polyamine depleted IEC-6 cells depends on Akt-mediated NF-kappaB activation but not GSK3beta activity. 1613 67

Protein kinase B and glycogen synthase kinase-3 have been identified as susceptibility genes for schizophrenia and altered protein and mRNA levels have been detected in the brains of schizophrenics post-mortem. Recently, we reported that haloperidol, clozapine and risperidone alter glycogen synthase kinase-3 and beta-catenin protein expression and glycogen synthase kinase-3 phosphorylation levels in the rat prefrontal cortex and striatum. In the current study, beta-catenin, adenomatous polyposis coli, Wnt1, dishevelled and glycogen synthase kinase-3 were examined in the ventral midbrain and hippocampus using western blotting. In addition, beta-catenin and GSK-3 were examined in the substantia nigra and ventral tegmental area using confocal and fluorescence microscopy. The results indicate that repeated antipsychotic administration results in significant elevations in glycogen synthase kinase-3, beta-catenin and dishevelled-3 protein levels in the ventral midbrain and hippocampus. Raclopride causes similar changes in beta-catenin and GSK-3 in the ventral midbrain, suggesting that D2 dopamine receptor antagonism mediated the changes observed following antipsychotic administration. In contrast, amphetamine, a drug capable of inducing psychotic episodes, had the opposite effect on beta-catenin and GSK-3 in the ventral midbrain. Collectively, the results suggest that antipsychotics may exert their beneficial effects through modifications to proteins that are associated with the canonical Wnt pathway.
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PMID:The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats. 1614 42

The recent findings demonstrating that insulin and leptin are expressed in and secreted by human ejaculated spermatozoa raise the controversial issue related to mRNA function in male gamete. Capacitated sperm display an increased metabolism and overall energy expenditure presumably to affect the changes in sperm signaling and function during capacitation. However the relationship between the signaling events associated with capacitation and the change in sperm metabolism energy is poorly understood. It emerges from the findings here reported that both leptin and insulin may be crucial in ejaculated spermatozoa to manage their energy status. Immunoistochemical analysis revealed that in uncapacitated sperm insulin was located at the subacrosomial level, in the midpiece and through the tail while leptin was immunodetected at the equatorial segment and at the midpiece. Capacitated sperm display an overall decrease and a more uniform distribution in the signal for both hormones and this is in agreement with their enhanced release in the medium. Both hormones in ejaculated sperm somehow recapitulate the cross-talk between their signalling transductional pathways in somatic cells, resulting in the increase of phosphoinositide 3-kinase (PI3K) activity, AKT S473 and Glycogen synthase kinase 3 (GSK-3)-S9 phosphorylations. During capacitation GSK-3 phosphorylation was abolished suggesting how in capacitating sperm there is a block in glycogen synthesis. This reasonably indicates how during capacitation glycogen reserve is mobilized and this makes the glucose as energy substrate available. For instance insulin dismissed by ejaculated spermatozoa up-regulates Glucose 6-Phosphate Dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway (PPP), which has be shown to be crucial in the acquisition of fertilizing capability as well as to mediate gamete fusion. Insulin immunoneutralization or blockage of its release, dramatically down regulated G6PDH. Interestingly, in the presence of a disruptor of insulin signaling wortmannin, an inhibitor of PI3K, the intrinsic activity of G6PDH drops. Leptin appears to play similar action to that of insulin on G6PDH in sperm (data in progress). The enhanced activity of this enzyme induced by both hormones produces an increase of NADPH that is essential for fatty acid synthesis from acetyl CoA. These fatty acids have two possible fates: beta-oxidation to produce ATP or reesterification back into triacylglycerol. Inter-relationships of the classes of substrates of free fatty acids (FFA) and glucose utilized for energy, has been long established [Randle, P.J., 1964. The interrelationships of hormones, fatty acid and glucose in the provision of energy. Postgrad. Med. J. 40, 457-463]. The authors observed in ejaculated spermatozoa what it occurs in somatic cells: FFA beta-oxidation tested utilizing the octanoil-CoA as substrate, appears to be stimulated by leptin and down-regulated by the contemporaneous presence of insulin in uncapacitated sperms. FFA beta-oxidation activity dramatically increases when capacitation starts, so it may be assumed the possibility that leptin may work to stimulate such enzymatic activity providing additional metabolic fuel to triggering capacitation process. The autonomous capability of sperm to release insulin and leptin suggests that they through an autocrine short loop may provide the recruitment of energy substrate according to sperm metabolic needs. This occurs independently by the systemic regulation and may represent a protective mechanism which preserves sperm fertilizing capability by any detrimental effects produced by long calorie restriction or by alterations occurring in the energy homeostasis at systemic level.
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PMID:Arguments raised by the recent discovery that insulin and leptin are expressed in and secreted by human ejaculated spermatozoa. 1627 24

The phosphatidylinositol 3-kinase pathway is an important regulator of a wide spectrum of tumor-related biological processes, including cell proliferation, survival, and motility, as well as neovascularization. Protein kinase B/Akt is activated in a complex manner through the phosphorylation of protein kinase B/Akt on Thr308 and Ser473. Although protein-dependent kinase-1 has been shown to phosphorylate Akt at Thr308, it is not clear whether there is a distinct kinase that exclusively phosphorylates Akt at Ser473. A possible candidate is integrin-linked kinase (ILK), which has been shown to phosphorylate Akt at Ser473 in vitro. ILK is a multidomain focal adhesion protein that is believed to be involved in signal transmission from integrin and growth factor receptors. Further, ILK is implicated in the regulation of anchorage-dependent cell growth/survival, cell cycle progression, invasion and migration, and tumor angiogenesis. In this study, we tested the hypothesis that ILK inhibition would inhibit these processes in gliomas in which it is constitutively expressed. We found that a newly developed small-molecule compound (QLT0267) effectively inhibited signaling through the ILK/Akt cascade in glioma cells by blocking the phosphorylation of Akt and downstream targets, including mammalian target of rapamycin and glycogen synthase kinase-3beta. Treatment of glioma cells with 12.5 micromol/L QLT0267 inhibited cell growth by 50% at 48 hours. An anchorage-dependent cell growth assay confirmed the cell growth-inhibitory effect of QLT0267. Further, the decrease in cell growth was associated with a dramatic accumulation of cells in the G2-M phase of the cell cycle. Although the cell growth-inhibitory effects of the ILK inhibitor were achieved only at a high concentration, the QLT0267 was able to reduce cellular invasion and angiogenesis at much lower concentrations as shown by in vitro invasion assays and vascular endothelial growth factor secretion. Thus, blocking the ILK/Akt pathway is a potential strategy for molecular targeted therapy for gliomas.
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PMID:Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma. 1627 89


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