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dc.contributor.authorSoutar, M.P.
dc.contributor.authorKim, W.Y.
dc.contributor.authorWilliamson, Ritchie
dc.contributor.authorPeggie, M.
dc.contributor.authorHastie, C.J.
dc.contributor.authorMcLauchlan, H.
dc.contributor.authorSnider, W.D.
dc.contributor.authorGordon-Weeks, P.R.
dc.contributor.authorSutherland, C.
dc.date.accessioned2014-04-28T11:21:23Z
dc.date.available2014-04-28T11:21:23Z
dc.date.issued2010
dc.identifier.citationSoutar MP, Kim WY, Williamson R et al (2010) Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain. Journal of Neurochemistry. 115(4): 974-983.
dc.identifier.urihttp://hdl.handle.net/10454/6201
dc.description.abstractMammalian glycogen synthase kinase-3 (GSK3) is generated from two genes, GSK3alpha and GSK3beta, while a splice variant of GSK3beta (GSK3beta2), containing a 13 amino acid insert, is enriched in neurons. GSK3alpha and GSK3beta deletions generate distinct phenotypes. Here, we show that phosphorylation of CRMP2, CRMP4, beta-catenin, c-Myc, c-Jun and some residues on tau associated with Alzheimer's disease, is altered in cortical tissue lacking both isoforms of GSK3. This confirms that they are physiological targets for GSK3. However, deletion of each GSK3 isoform produces distinct substrate phosphorylation, indicating that each has a different spectrum of substrates (e.g. phosphorylation of Thr509, Thr514 and Ser518 of CRMP is not detectable in cortex lacking GSK3beta, yet normal in cortex lacking GSK3alpha). Furthermore, the neuron-enriched GSK3beta2 variant phosphorylates phospho-glycogen synthase 2 peptide, CRMP2 (Thr509/514), CRMP4 (Thr509), Inhibitor-2 (Thr72) and tau (Ser396), at a lower rate than GSK3beta1. In contrast phosphorylation of c-Myc and c-Jun is equivalent for each GSK3beta isoform, providing evidence that differential substrate phosphorylation is achieved through alterations in expression and splicing of the GSK3 gene. Finally, each GSK3beta splice variant is phosphorylated to a similar extent at the regulatory sites, Ser9 and Tyr216, and exhibit identical sensitivities to the ATP competitive inhibitor CT99021, suggesting upstream regulation and ATP binding properties of GSK3beta1 and GSK3beta2 are similar.
dc.relation.isreferencedbyhttp://dx.doi.org/10.1111/j.1471-4159.2010.06988.x
dc.subjectAlzheimer disease; Enzymology; Genetics; Metabolism
dc.subject; Amino acid sequence
dc.subject; Animals
dc.subject; Brain
dc.subject; Cell line
dc.subject; Glycogen synthase kinase 3
dc.subject; Humans
dc.subject; Isoenzymes
dc.subject; Mice
dc.subject; Knockout
dc.subject; Transgenic
dc.subject; Molecular sequence data
dc.subject; Phosphorylation
dc.subject; Substrate specificity
dc.subject; REF 2014
dc.titleEvidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain
dc.typeArticle


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