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Molecular Pharmacology

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Research ArticleArticle

Nerve Growth Factor Stimulation of p42/p44 Mitogen-Activated Protein Kinase in PC12 Cells: Role of Gi/o, G Protein-Coupled Receptor Kinase 2, β-Arrestin I, and Endocytic Processing

Soma Rakhit, Susan Pyne and Nigel J. Pyne
Molecular Pharmacology July 2001, 60 (1) 63-70; DOI: https://doi.org/10.1124/mol.60.1.63
Soma Rakhit
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Susan Pyne
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Nigel J. Pyne
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Abstract

In this study, we have shown that nerve growth factor (NGF)-dependent activation of the p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) pathway in PC12 cells can be partially blocked by pertussis toxin (which inactivates the G proteins Gi/o). This suggests that the Trk A receptor may use a G protein-coupled receptor pathway to signal to p42/p44 MAPK. This was supported by data showing that the NGF-dependent activation of p42/p44 MAPK is potentiated in cells transfected with G protein-coupled receptor kinase 2 (GRK2) or β-arrestin I. Moreover, GRK2 is constitutively bound with the Trk A receptor, whereas NGF stimulates the pertussis toxin-sensitive binding of β-arrestin I to the TrkA receptor-GRK2 complex. Both GRK2 and β-arrestin I are involved in clathrin-mediated endocytic signaling to p42/p44 MAPK. Indeed, inhibitors of clathrin-mediated endocytosis (e.g., monodansylcadaverine, concanavalin A, and hyperosmolar sucrose) reduced the NGF-dependent activation of p42/p44 MAPK. Finally, we have found that the G protein-coupled receptor-dependent component regulating p42/p44 MAPK is required for NGF-induced differentiation of PC12 cells. Thus, NGF-dependent inhibition of DNA synthesis was partially blocked by PD098059 (inhibitor of MAPK kinase-1 activation) and pertussis toxin. Our findings are the first to show that the Trk A receptor uses a classic G protein-coupled receptor-signaling pathway to promote differentiation of PC12 cells.

  • Abbreviations

    NGF
    nerve growth factor
    MAPK
    mitogen-activated protein kinase
    IGF
    insulin-like growth factor
    GRK
    G protein-coupled receptor kinase
    Grb-2
    growth factor receptor binding protein
    PI3K
    phosphoinositide 3-kinase
    LPA
    lysophosphatidic acid
    PDGF
    platelet-derived growth factor
    Gi
    inhibitory G protein
    Gab1
    growth factor receptor binding protein associated binder
    HRP
    horseradish peroxidase
    DMEM
    Dulbecco's modified Eagle's medium
    FCS
    fetal calf serum
    NP-40
    Nonidet P-40
    EGF
    epidermal growth factor
    GPCR
    G protein-coupled receptor
    mSos
    son of sevenless
    c-Src
    cellular Src tyrosine kinase
    MDC
    monodansylcadaverine
    • Received August 25, 2000.
    • Accepted February 9, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    Nerve Growth Factor Stimulation of p42/p44 Mitogen-Activated Protein Kinase in PC12 Cells: Role of Gi/o, G Protein-Coupled Receptor Kinase 2, β-Arrestin I, and Endocytic Processing

    Soma Rakhit, Susan Pyne and Nigel J. Pyne
    Molecular Pharmacology July 1, 2001, 60 (1) 63-70; DOI: https://doi.org/10.1124/mol.60.1.63

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    Research ArticleArticle

    Nerve Growth Factor Stimulation of p42/p44 Mitogen-Activated Protein Kinase in PC12 Cells: Role of Gi/o, G Protein-Coupled Receptor Kinase 2, β-Arrestin I, and Endocytic Processing

    Soma Rakhit, Susan Pyne and Nigel J. Pyne
    Molecular Pharmacology July 1, 2001, 60 (1) 63-70; DOI: https://doi.org/10.1124/mol.60.1.63
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