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Literature summary for 2.7.11.26 extracted from

  • Hanger, D.P.; Noble, W.
    Functional implications of glycogen synthase kinase-3-mediated tau phosphorylation (2011), Int. J. Alzheimers Dis., 2011, 352805.
    View publication on PubMedView publication on EuropePMC

Activating Compound

Activating Compound Comment Organism Structure
14-3-3 protein 14-3-3 recognises GSK-3 phosphorylated at Ser9, and the association of tau with this complex is believed to regulate its phosphorylation by GSK-3, since in human embryonic kidney cells, tau phosphorylation by GSK-3 is suppressed in the absence of 14-3-3, but GSK-3 is active and phosphorylates tau if 14-3-3 is present Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
GSK-3 exists as two isoforms, alpha and beta, which share 85% sequence identity and are encoded by distinct genes located on chromosomes 19 and 3, respectively. Isozyme GSK-3beta occurs in two splicing variants, GSK-3beta1 and GSK-3beta2, that differ by the presence of an additional insertion of 13 amino acids Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
SB-415286
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Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + [tau-protein] Homo sapiens tau isoforms in the human central nervous system and GSK-3 phosphorylation sites. Isozymes GSK-3alpha and GSK-3beta1/2 differentially phosphorylate tau, e.g. Ser396 in tau is phosphorylated by both splice variants, whereas Ser199 is a significant target of GSK-3beta1, but not of GSK-3beta2 activity ADP + O-phospho-[tau-protein]
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?

Organism

Organism UniProt Comment Textmining
Homo sapiens P49841
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-

Posttranslational Modification

Posttranslational Modification Comment Organism
phosphoprotein 14-3-3 recognises GSK-3 phosphorylated at Ser9, and indeed GSK-3 in this complex is phosphorylated at Ser9 in brain Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
brain in brain, tau exists in a complex with GSK-3 and the scaffolding protein 14-3-3 Homo sapiens
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central nervous system
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Homo sapiens
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additional information isozyme GSK-3beta slicing variant GSK-3beta2 is enriched in neurons, where it is present in cell bodies, neuritis, and growth cones Homo sapiens
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neuron
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Homo sapiens
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Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + [tau-protein] tau isoforms in the human central nervous system and GSK-3 phosphorylation sites. Isozymes GSK-3alpha and GSK-3beta1/2 differentially phosphorylate tau, e.g. Ser396 in tau is phosphorylated by both splice variants, whereas Ser199 is a significant target of GSK-3beta1, but not of GSK-3beta2 activity Homo sapiens ADP + O-phospho-[tau-protein]
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?
ATP + [tau-protein] the enzyme phosphorylates in tau residues S46, T50, S69, and T71 at the N-terminus, residues T149, T153, T175, T181, S184, S195, S198, S199, S202, T205, S210, T212, S214, T217, T220, T231, S235, S237, S241, and T245 in the central, proline-rich domain, residues S258 and S262 in the repeat domain R1 domain, residues S285, S289, and S324 in the repeat domain R2 domain, and residues S352, S356, T373, S396, S400, S404, S409, and S413 in the repeat domain R4 domain, there are no phosphorylation sites of GSK-3 in the repeat domain R3 domain, overview Homo sapiens ADP + O-phospho-[tau-protein]
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additional information tau possesses 80 phosphorylatable serine and threonine residues Homo sapiens ?
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?

Synonyms

Synonyms Comment Organism
glycogen synthase kinase-3
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Homo sapiens
GSK-3
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Homo sapiens

Cofactor

Cofactor Comment Organism Structure
ATP
-
Homo sapiens

General Information

General Information Comment Organism
malfunction comparison of phosphorylation sites in human Alzheimer and control brain with recombinant tau phosphorylated by GSK-3 in vitro, several sites are not phosphrylated in Alzheimer's disease samples, overview. Inhibiting GSK-3 with SB-415286 also protects cultured neurons from cell death induced by reduced phosphatidylinositol 3-kinase activity, and this protection is paralleled by decreased tau phosphorylation Homo sapiens
additional information isozymes GSK-3alpha and GSK-3beta share many substrates and appear to be able to compensate partially for each other, although they also appear to have distinct functions Homo sapiens
physiological function tau is primarily a neuronal microtubule-associated protein that has functions related to the stabilisation of microtubules. Phosphorylation of tau is usually a very rapid and reversible process, which is mediated by the opposing actions of several protein kinases and phosphatases. Tau phosphorylation is increased during embryonic development, and in neurodegenerative conditions. Phosphorylation of tau is an important dynamic and regulatory element involved in the binding of tau to tubulin, ole for GSK-3 activity on physiological tau function and on tau dysfunction in neurodegenerative disease, glycogen synthase kinase-3 activity and tau function in normal and diseased brain, detailed overview. In neurons, the primary location of tau is in axons, where it is presumed to act as a stabilising protein for the microtubule cytoskeleton. Tau has an important function in maintaining microtubule dynamic instability, through dual processes that result in the lengthening and shortening of microtubules in response to external signals. Increased tau phosphorylation leads to its detachment from tubulin, thereby, enhancing microtubule disassembly and reducing microtubule stability. Highly phosphorylated forms of tau bind less well to microtubules, resulting in a loss of the microtubule-stabilising properties of tau and ultimately the collapse of the neuronal cytoskeleton. Tau phosphorylation also influences the positioning of tau in dendrites, and the association of tau with plasma membranes and nuclei. Elevated phosphorylation results in the relocalisation of tau fromaxons into the somatodendritic region of neurons. Protein 14-3-3 recognises GSK-3 phosphorylated at Ser9, and the association of tau with this complex is believed to regulate its phosphorylation by GSK-3, since in human embryonic kidney cells, tau phosphorylation by GSK-3 is suppressed in the absence of 14-3-3, but GSK-3 is active and phosphorylates tau if 14-3-3 is present. The phosphorylation of tau by GSK-3 reduces the ability of tau to promote microtubule assembly in vitro and in cells. Priming of tau for GSK-3 phosphorylation is frequently provided by the activity of PKA, CK1, or CK2 on unphosphorylated substrates, although other kinases, such as members of the mitogen-activated protein kinase family, or cdk5, can also initiate priming on some GSK-3 substrates. GSK-3 remains a principal candidate kinase for both physiological and pathological tau phosphorylation, overview. GSK-3 in cells is important for the maintenance of healthy functional neurons, and changes in tau phosphorylation are likely be indicative of reduced neuronal viability Homo sapiens