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Regulation of Glycogen Synthase kinase 3beta by phosphorylation and O-beta-linked N-acetylglucosaminylation: implications on tau protein phosphorylation

ABSTRACT: Glycogen synthase kinase 3 (GSK3) plays a pivotal role in signaling pathways related to insulin metabolism and in the pathogenesis of Alzheimer s disease (AD) and other neurodegenerative disorders. More particularly, the GSK3beta isoform is involved in AD-associated tau pathology as one of the major kinases involved in the hyperphosphorylation of the microtubule-associated tau protein, one of the neuropathological hallmarks of AD. As a constitutively active serine/threonine proline-directed kinase, GSK3 is inactivated by Akt/PKB-mediated phosphorylation of Ser9 at the N-terminal disordered domain. Furthermore, GSK3 activity requires for most of its substrates a priming (pre-phosphorylation) by another kinase that allows binding of the substrate in a phosphate-specific pocket near to the active site. It has been shown that GSK3 is also post-translationally modified by O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) with still unknown functional implications. We have found that binding of the phosphorylated, active form of Akt inhibits GSK3beta kinase activity on both primed and unprimed tau substrates, and Akt-mediated Ser9 phosphorylation restores the GSK3beta kinase activity on primed tau only. Therefore, Ser9 phosphorylation only inactivates GSK3 kinase activity on an unprimed substrate. Additionally, we have shown that GSK3beta is O-GlcNAcylated at multiple sites in both its disordered N- and C-terminal domains including Ser9, but O-GlcNAcylation does not alter kinase activity nor the Akt-mediated regulation of GSK3.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Caroline Smet-Nocca

PROVIDER: MSV000094049 | MassIVE | Fri Feb 09 05:36:00 GMT 2024

REPOSITORIES: MassIVE

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Regulation of Glycogen Synthase Kinase-3β by Phosphorylation and O-β-Linked N-Acetylglucosaminylation: Implications on Tau Protein Phosphorylation.

El Hajjar Léa L Page Adeline A Bridot Clarisse C Cantrelle François-Xavier FX Landrieu Isabelle I Smet-Nocca Caroline C

Biochemistry 20240524 12

Glycogen synthase kinase 3 (GSK3) plays a pivotal role in signaling pathways involved in insulin metabolism and the pathogenesis of neurodegenerative disorders. In particular, the GSK3β isoform is implicated in Alzheimer's disease (AD) as one of the key kinases involved in the hyperphosphorylation of tau protein, one of the neuropathological hallmarks of AD. As a constitutively active serine/threonine kinase, GSK3 is inactivated by Akt/PKB-mediated phosphorylation of Ser9 in the N-terminal disor ...[more]

PMID: 38788673

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