Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly phosphorylated tau protein is the main component of paired helical filaments (PHF), which comprise the neurofibrillary tangles (NFT) in some neurons of patients with Alzheimer disease (AD). Glycogen synthase kinase 3 (GSK3) phosphorylates tau in vitro at several sites also found to be phosphorylated in PHF-tau; tau is phosphorylated at these sites in both AD and normal control (NC) brains, although the extent of phosphorylation is far greater in tau from AD. If GSK3 levels are increased in AD, then tau phosphorylation and perhaps PHF formation may occur. To quantify GSK3, blots of AD and NC brain supernatant and particulate fractions were probed with antibodies to GSK3. In particulate fractions of AD compared to NC, GSK3 alpha immunoreactivity did not increase, but in fact, decreased 40%, and GSK3 beta immunoreactivity decreased 30%. GSK3 alpha and GSK3 beta levels correlated well with each other. GSK3 levels correlated negatively with numbers of NFT.
Mol Chem Neuropathol
PMID:Glycogen synthase kinase 3 alteration in Alzheimer disease is related to neurofibrillary tangle formation. 897

MITF (microphthalmia-associated transcription factor) is a basic-helix-loop-helix-leucine zipper (bHLHZip) factor which regulates expression of tyrosinase and other melanocytic genes via a CATGTG promoter sequence, and is involved in melanocyte differentiation. Mutations of MITF in mice or humans with Waardenburg syndrome type 2 (WS2) often severely disrupt the bHLHZip domain, suggesting the importance of this structure. Here, we show that Ser298, which locates downstream of the bHLHZip and was previously found to be mutated in individuals with WS2, plays an important role in MITF function. Glycogen synthase kinase 3 (GSK3) was found to phosphorylate Ser298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter. The same serine was found to be phosphorylated in vivo, and expression of dominant-negative GSK3beta selectively suppressed the ability of MITF to transactivate the tyrosinase promoter. Moreover, mutation of Ser298, as found in a WS2 family, disabled phos-phorylation of MITF by GSK3beta and impaired MITF function. These findings suggest that the Ser298 is important for MITF function and is phosphorylated probably by GSK3beta.
Hum Mol Genet 2000 Jan 01
PMID:Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. 1058 87

Glycogen synthase kinase 3 (GSK3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention.
Nat Rev Mol Cell Biol 2001 Oct
PMID:The renaissance of GSK3. 1158 4

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a key target in drug discovery. It has been implicated in multiple cellular processes and linked with the pathogenesis of several diseases. GSK-3 inhibitors might prove useful as therapeutic compounds in the treatment of conditions associated with elevated levels of enzyme activity, such as type 2 diabetes and Alzheimer's disease. The pro-apoptotic feature of GSK-3 activity suggests a potential role for its inhibitors in protection against neuronal cell death, and in the treatment of traumatic head injury and stroke. Finally, selective inhibitors of GSK-3 could mimic the action of mood stabilizers such as lithium and valproic acid and be used in the treatment of bipolar mood disorders.
Trends Mol Med 2002 Mar
PMID:Glycogen synthase kinase 3: an emerging therapeutic target. 1187 73

Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase that is involved in multiple cellular signaling pathways, including the Wnt signaling cascade where it phosphorylates beta-catenin, thus targeting it for proteasome-mediated degradation. Unlike phosphorylation of glycogen synthase, phosphorylation of beta-catenin by GSK-3 does not require priming in vitro, i.e. it is not dependent on the presence of a phosphoserine, four residues C-terminal to the GSK-3 phosphorylation site. Recently, a means of dissecting GSK-3 activity toward primed and non-primed substrates has been made possible by identification of the R96A mutant of GSK-3beta. This mutant is unable to phosphorylate primed but can still phosphorylate unprimed substrates (Frame, S., Cohen, P., and Biondi R. M. (2001) Mol. Cell 7, 1321-1327). Here we have investigated whether phosphorylation of Ser(33), Ser(37), and Thr(41) in beta-catenin requires priming through prior phosphorylation at Ser(45) in intact cells. We have shown that the Arg(96) mutant does not induce beta-catenin degradation but instead stabilizes beta-catenin, indicating that it is unable to phosphorylate beta-catenin in intact cells. Furthermore, if Ser(45) in beta-catenin is mutated to Ala, beta-catenin is markedly stabilized, and phosphorylation of Ser(33), Ser(37), and Thr(41) in beta-catenin by wild type GSK-3beta is prevented in intact cells. In addition, we have shown that the L128A mutant, which is deficient in phosphorylating Axin in vitro, is still able to phosphorylate beta-catenin in intact cells although it has reduced activity. Mutation of Tyr(216) to Phe markedly reduces the ability of GSK-3beta to phosphorylate and down-regulate beta-catenin. In conclusion, we have found that the Arg(96) mutant has a dominant-negative effect on GSK-3beta-dependent phosphorylation of beta-catenin and that targeting of beta-catenin for degradation requires prior priming through phosphorylation of Ser(45).
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PMID:Expression and characterization of GSK-3 mutants and their effect on beta-catenin phosphorylation in intact cells. 1196 63

Glycogen synthase kinase-3beta (GSK3beta) is a central figure in many intracellular signaling systems and is directly regulated by lithium. Substantial evidence now indicates that an important property of the mood stabilizer, lithium, is to influence GSK3beta-linked signaling pathways. This raises the possibility that other mood stabilizers act in a similar manner, which may include modulation of signaling systems leading to GSK3beta, direct regulation of GSK3beta or regulation of signaling intermediates downstream of GSK3beta. Downstream targets of GSK3beta, and thus potential targets of mood stabilizers, are several key transcription factors, including beta-catenin, AP-1, cyclic AMP-response element binding protein, NFkappaB, Myc, heat shock factor-1, nuclear factor of activated T-cells and CCAAT/enhancer-binding proteins. GSK3beta also is an important modulator of cell death, which may be a consequence of its regulatory effects on transcription factor activities. GSK3beta facilitates apoptosis, and lithium's inhibition of GSK3beta supports cell survival. Thus, signaling systems determining cell fate appear to be important targets of mood stabilizers, and these may include signaling pathways encompassing GSK3beta, including transcription factors regulated by GSK3beta.
Mol Psychiatry 2002
PMID:Mood stabilizers, glycogen synthase kinase-3beta and cell survival. 1198 94

Glycogen is an important storage reserve of glucose present in many organisms, from bacteria to humans. Its biosynthesis is initiated by a specialized protein, glycogenin, which has the unusual property of transferring glucose from UDP-glucose to form an oligosaccharide covalently attached to itself at Tyr194. Glycogen synthase and the branching enzyme complete the synthesis of the polysaccharide. The structure of glycogenin was solved in two different crystal forms. Tetragonal crystals contained a pentamer of dimers in the asymmetric unit arranged in an improper non-crystallographic 10-fold relationship, and orthorhombic crystals contained a monomer in the asymmetric unit that is arranged about a 2-fold crystallographic axis to form a dimer. The structure was first solved to 3.4 A using the tetragonal crystal form and a three-wavelength Se-Met multi-wavelength anomalous diffraction (MAD) experiment. Subsequently, an apo-enzyme structure and a complex between glycogenin and UDP-glucose/Mn2+ were solved by molecular replacement to 1.9 A using the orthorhombic crystal form. Glycogenin contains a conserved DxD motif and an N-terminal beta-alpha-beta Rossmann-like fold that are common to the nucleotide-binding domains of most glycosyltransferases. Although sequence identity amongst glycosyltransferases is minimal, the overall folds are similar. In all of these enzymes, the DxD motif is essential for coordination of the catalytic divalent cation, most commonly Mn2+. We propose a mechanism in which the Mn2+ that associates with the UDP-glucose molecule functions as a Lewis acid to stabilize the leaving group UDP and to facilitate the transfer of the glucose moiety to an intermediate nucleophilic acceptor in the enzyme active site, most likely Asp162. Following transient transfer to Asp162, the glucose moiety is then delivered to the final acceptor, either directly to Tyr194 or to glucose residues already attached to Tyr194. The positioning of the bound UDP-glucose far from Tyr194 in the glycogenin structure raises questions as to the mechanism for the attachment of the first glucose residues. Possibly the initial glucosylation is via inter-dimeric catalysis with an intra-molecular mechanism employed later in oligosaccharide synthesis.
J Mol Biol 2002 May 31
PMID:Crystal structure of the autocatalytic initiator of glycogen biosynthesis, glycogenin. 1205 21

Intracellular regulation of oocyte meiosis is not completely understood. However, reversible phosphorylation, which involves serine/threonine protein kinases and phosphatases (PP), is an important mediator. Glycogen synthase kinase-3 (GSK-3) is a highly conserved serine/threonine protein kinase. Currently no reports exist on presence or function of GSK-3 in mammalian oocytes. The aim of this study was to determine GSK-3 presence/absence, transcript and protein expression, intracellular protein distribution, and to investigate the functional importance of GSK-3 in mouse oocyte meiosis. Germinal vesicle-intact (GVI) oocytes contained both GSK-3 transcript and protein. Although GSK-3 beta-isoform is the only transcript identifiable in GVI oocytes, both alpha- and beta-isoforms were recognized by Western blot analysis. In growing, meiotic-incompetent oocytes GSK-3 was present, diffusely located throughout the cytoplasm and absent in the nucleus, whereas in meiotic-competent oocytes this cytoplasmic GSK-3 displays a predominant peri-oolemma staining. Treatment of mouse GVI oocytes with lithium chloride (LiCl), which inhibits both inositol monophosphatase (IMPase) and GSK-3, had no significant influence on oocyte viability, morphology, or development to metaphase II (MII). However, LiCl caused abnormal spindle formation and significantly increased incidence of abnormal homologue segregation during the first meiotic division. L690,330, which is a specific IMPase inhibitor, had no significant effect on oocyte viability, morphology, MII development, or homologue segregation. This is the first report of GSK-3 in mammalian oocytes. LiCl inhibition of mouse oocyte GSK-3 modified organization of microtubules and/or function of meiotic spindles thus compromising segregation of condensed bivalent chromosomes.
Mol Reprod Dev 2003 Jan
PMID:Glycogen synthase kinase-3 regulates mouse oocyte homologue segregation. 1242 Mar 4

Glycogen synthase kinase 3 (GSK-3) is a protein kinase that plays essential roles in the control of several developmental, metabolic, and apoptotic processes. Owing to its negative actions on several oncogenic insults, it has been considered a putative functional tumor suppressor. We studied the expression, activity, and localization of GSK-3beta during the process of chemically induced two-stage mouse skin carcinogenesis and also in the tumors generated upon subcutaneous injection of Akt-transformed keratinocytes. We found that GSK-3 activity was downregulated at the later stages of promotion by tyrosine 216 dephosphorylation and serine 9 phosphorylation. The data obtained with Akt-transformed keratinocytes clearly suggested the involvement of Akt in serine 9 phosphorylation of GSK-3beta. Finally, besides functional inactivation, significant basal activity of GSK-3beta was detected in all cases, indicating that this enzyme provides essential functions to malignant keratinocytes.
Mol Carcinog 2002 Dec
PMID:Expression, localization, and activity of glycogen synthase kinase 3beta during mouse skin tumorigenesis. 1248 9

Recent studies have revealed a positive correlation between astrocyte apoptosis and rapid disease progression in persons with neurodegenerative diseases. Glycogen synthase kinase 3beta (GSK-3beta) is a molecular regulator of cell fate in the central nervous system and a target of the phosphatidylinositol 3-kinase (PI-3K) pathway. We have therefore examined the role of the PI-3K pathway, and of GSK-3beta, in regulating astrocyte survival. Our studies indicate that inhibition of PI-3K leads to apoptosis in primary cortical astrocytes. Furthermore, overexpression of a constitutively active GSK-3beta mutant (S9A) is sufficient to cause astrocyte apoptosis, whereas an enzymatically inactive GSK-3beta mutant (K85M) has no effect. In light of reports on the interplay between GSK-3beta and nuclear factor kappaB (NF-kappaB), and because of the antiapoptotic activity of NF-kappaB, we examined the effect of GSK-3beta overexpression on NF-kappaB activation. These experiments revealed strong inhibition of NF-kappaB activation in astrocytes upon overexpression of the S9A, but not the K85M, mutant of GSK-3beta. This was accompanied by stabilization of the NF-kappaB-inhibitory protein, IkappaBalpha and down-regulation of IkappaB kinase (IKK) activity. These findings therefore implicate GSK-3beta as a regulator of NF-kappaB activation in astrocytes and suggest that the pro-apoptotic effects of GSK-3beta may be mediated at least in part through the inhibition of NF-kappaB pathway.
Mol Cell Biol 2003 Jul
PMID:Glycogen synthase kinase 3beta-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kappaB signaling. 1280 4


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