Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo

A R Cole, F Causeret, G Yadirgi, C J Hastie, H Mclauchlan, E J McManus, F Hernandez, B J Eickholt, M Nikolic, C Sutherland, Calum Sutherland

    Research output: Contribution to journalArticle

    146 Citations (Scopus)

    Abstract

    Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched proteins that regulate neurite outgrowth and growth cone dynamics. Here, we show that Cdk5 phosphorylates CRMP1, CRMP2, and CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 phosphorylates and primes CRMP4 only. The Cdk5 and DYRK2 inhibitor purvalanol decreases the phosphorylation of CRMP proteins in neurons, whereas CRMP1 and CRMP2, but not CRMP4, phosphorylation is decreased in Cdk5(-/-) cortices. Stimulation of neuroblastoma cells with IGF1 or TPA decreases GSK3 activity concomitantly with CRMP2 and CRMP4 phosphorylation. Conversely, increased GSK3 activity is not sufficient to increase CRMP phosphorylation. However, the growth cone collapse-inducing protein Sema3A increases Cdk5 activity and promotes phosphorylation of CRMP2 ( but not CRMP4). Therefore, inhibition of GSK3 alters phosphorylation of all CRMP isoforms; however, individual isoforms can be differentially regulated by their respective priming kinase. This is the first GSK3 substrate found to be regulated in this manner and may explain the hyperphosphorylation of CRMP2 observed in Alzheimer's disease.

    Original languageEnglish
    Pages (from-to)16591-16598
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume281
    Issue number24
    DOIs
    Publication statusPublished - 16 Jun 2006

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    Semaphorin-3A
    Glycogen Synthase Kinase 3
    Phosphorylation
    Phosphotransferases
    Proteins
    Growth Cones
    Neurons
    Cones
    Protein Isoforms
    Neuroblastoma
    Alzheimer Disease
    Substrates

    Cite this

    Cole, A R ; Causeret, F ; Yadirgi, G ; Hastie, C J ; Mclauchlan, H ; McManus, E J ; Hernandez, F ; Eickholt, B J ; Nikolic, M ; Sutherland, C ; Sutherland, Calum. / Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 24. pp. 16591-16598.
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    abstract = "Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched proteins that regulate neurite outgrowth and growth cone dynamics. Here, we show that Cdk5 phosphorylates CRMP1, CRMP2, and CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 phosphorylates and primes CRMP4 only. The Cdk5 and DYRK2 inhibitor purvalanol decreases the phosphorylation of CRMP proteins in neurons, whereas CRMP1 and CRMP2, but not CRMP4, phosphorylation is decreased in Cdk5(-/-) cortices. Stimulation of neuroblastoma cells with IGF1 or TPA decreases GSK3 activity concomitantly with CRMP2 and CRMP4 phosphorylation. Conversely, increased GSK3 activity is not sufficient to increase CRMP phosphorylation. However, the growth cone collapse-inducing protein Sema3A increases Cdk5 activity and promotes phosphorylation of CRMP2 ( but not CRMP4). Therefore, inhibition of GSK3 alters phosphorylation of all CRMP isoforms; however, individual isoforms can be differentially regulated by their respective priming kinase. This is the first GSK3 substrate found to be regulated in this manner and may explain the hyperphosphorylation of CRMP2 observed in Alzheimer's disease.",
    author = "Cole, {A R} and F Causeret and G Yadirgi and Hastie, {C J} and H Mclauchlan and McManus, {E J} and F Hernandez and Eickholt, {B J} and M Nikolic and C Sutherland and Calum Sutherland",
    note = "dc.publisher: American Society for Biochemistry and Molecular Biology This work established that CRMP2 modification by GSK3 in vivo was dependent on ‘priming' by CDK5. However, the closely related isoform CRMP4 was not thereby establishing a novel paradigm in GSK3 action and providing a mechanism for isoform specific modulation. I was grant holder, designed the experiments and wrote paper.",
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    Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. / Cole, A R ; Causeret, F ; Yadirgi, G ; Hastie, C J ; Mclauchlan, H ; McManus, E J ; Hernandez, F ; Eickholt, B J ; Nikolic, M ; Sutherland, C ; Sutherland, Calum.

    In: Journal of Biological Chemistry, Vol. 281, No. 24, 16.06.2006, p. 16591-16598.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo

    AU - Cole, A R

    AU - Causeret, F

    AU - Yadirgi, G

    AU - Hastie, C J

    AU - Mclauchlan, H

    AU - McManus, E J

    AU - Hernandez, F

    AU - Eickholt, B J

    AU - Nikolic, M

    AU - Sutherland, C

    AU - Sutherland, Calum

    N1 - dc.publisher: American Society for Biochemistry and Molecular Biology This work established that CRMP2 modification by GSK3 in vivo was dependent on ‘priming' by CDK5. However, the closely related isoform CRMP4 was not thereby establishing a novel paradigm in GSK3 action and providing a mechanism for isoform specific modulation. I was grant holder, designed the experiments and wrote paper.

    PY - 2006/6/16

    Y1 - 2006/6/16

    N2 - Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched proteins that regulate neurite outgrowth and growth cone dynamics. Here, we show that Cdk5 phosphorylates CRMP1, CRMP2, and CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 phosphorylates and primes CRMP4 only. The Cdk5 and DYRK2 inhibitor purvalanol decreases the phosphorylation of CRMP proteins in neurons, whereas CRMP1 and CRMP2, but not CRMP4, phosphorylation is decreased in Cdk5(-/-) cortices. Stimulation of neuroblastoma cells with IGF1 or TPA decreases GSK3 activity concomitantly with CRMP2 and CRMP4 phosphorylation. Conversely, increased GSK3 activity is not sufficient to increase CRMP phosphorylation. However, the growth cone collapse-inducing protein Sema3A increases Cdk5 activity and promotes phosphorylation of CRMP2 ( but not CRMP4). Therefore, inhibition of GSK3 alters phosphorylation of all CRMP isoforms; however, individual isoforms can be differentially regulated by their respective priming kinase. This is the first GSK3 substrate found to be regulated in this manner and may explain the hyperphosphorylation of CRMP2 observed in Alzheimer's disease.

    AB - Collapsin response mediator proteins (CRMPs) are a family of neuron-enriched proteins that regulate neurite outgrowth and growth cone dynamics. Here, we show that Cdk5 phosphorylates CRMP1, CRMP2, and CRMP4, priming for subsequent phosphorylation by GSK3 in vitro. In contrast, DYRK2 phosphorylates and primes CRMP4 only. The Cdk5 and DYRK2 inhibitor purvalanol decreases the phosphorylation of CRMP proteins in neurons, whereas CRMP1 and CRMP2, but not CRMP4, phosphorylation is decreased in Cdk5(-/-) cortices. Stimulation of neuroblastoma cells with IGF1 or TPA decreases GSK3 activity concomitantly with CRMP2 and CRMP4 phosphorylation. Conversely, increased GSK3 activity is not sufficient to increase CRMP phosphorylation. However, the growth cone collapse-inducing protein Sema3A increases Cdk5 activity and promotes phosphorylation of CRMP2 ( but not CRMP4). Therefore, inhibition of GSK3 alters phosphorylation of all CRMP isoforms; however, individual isoforms can be differentially regulated by their respective priming kinase. This is the first GSK3 substrate found to be regulated in this manner and may explain the hyperphosphorylation of CRMP2 observed in Alzheimer's disease.

    U2 - 10.1074/jbc.M513344200

    DO - 10.1074/jbc.M513344200

    M3 - Article

    VL - 281

    SP - 16591

    EP - 16598

    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

    IS - 24

    ER -