GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons

A R Cole, A Knebel, N A Morrice, L A Robertson, A J Irving, Chris N. Connolly, Calum Sutherland

    Research output: Contribution to journalArticle

    189 Citations (Scopus)

    Abstract

    Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from Alzheimer brain. Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, a GSK-3-insensitive CRMP2 mutant has dramatically reduced ability to promote axon elongation, a similar effect to pharmacological inhibition of GSK-3. Hence, we propose that phosphorylation of CRMP proteins by GSK-3 regulates axon elongation. This work provides a direct connection between hyperphosphorylation of these residues and elevated GSK-3 activity, both of which are observed in Alzheimer brain.
    Original languageEnglish
    Pages (from-to)50176-50180
    Number of pages5
    JournalJournal of Biological Chemistry
    Volume279
    Issue number48
    DOIs
    Publication statusPublished - 26 Nov 2004

    Fingerprint

    Semaphorin-3A
    Glycogen Synthase Kinase 3
    Phosphorylation
    Neurons
    Axons
    Epitopes
    Elongation
    Proteins
    Brain
    Aptitude
    Neuroblastoma
    Alzheimer Disease
    Pharmacology
    Amino Acids
    Substrates

    Cite this

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    title = "GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons",
    abstract = "Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from Alzheimer brain. Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, a GSK-3-insensitive CRMP2 mutant has dramatically reduced ability to promote axon elongation, a similar effect to pharmacological inhibition of GSK-3. Hence, we propose that phosphorylation of CRMP proteins by GSK-3 regulates axon elongation. This work provides a direct connection between hyperphosphorylation of these residues and elevated GSK-3 activity, both of which are observed in Alzheimer brain.",
    author = "Cole, {A R} and A Knebel and Morrice, {N A} and Robertson, {L A} and Irving, {A J} and Connolly, {Chris N.} and Calum Sutherland",
    note = "dc.publisher: American Society for Biochemistry and Molecular Biology This was the first demonstration that the Alzheimer's associated protein CRMP was targeted by GSK3, and detailed the molecular mechanism by which the Alzheimer's associated epitope was generated. The GSK3/CRMP2 interaction became a novel target for Alzheimer's therapy. I was grant holder, designed the experiments and wrote the paper",
    year = "2004",
    month = "11",
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    language = "English",
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    GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons. / Cole, A R ; Knebel, A ; Morrice, N A ; Robertson, L A ; Irving, A J ; Connolly, Chris N.; Sutherland, Calum.

    In: Journal of Biological Chemistry, Vol. 279, No. 48, 26.11.2004, p. 50176-50180.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons

    AU - Cole, A R

    AU - Knebel, A

    AU - Morrice, N A

    AU - Robertson, L A

    AU - Irving, A J

    AU - Connolly, Chris N.

    AU - Sutherland, Calum

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    AB - Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from Alzheimer brain. Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, a GSK-3-insensitive CRMP2 mutant has dramatically reduced ability to promote axon elongation, a similar effect to pharmacological inhibition of GSK-3. Hence, we propose that phosphorylation of CRMP proteins by GSK-3 regulates axon elongation. This work provides a direct connection between hyperphosphorylation of these residues and elevated GSK-3 activity, both of which are observed in Alzheimer brain.

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