Gö 6976 Is a Potent Inhibitor of Neurotrophin-Receptor Intrinsic Tyrosine Kinase

Authors

  • M. Margarita Behrens,

    1. Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
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  • Uta Strasser,

    1. Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
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  • D. W. Choi

    1. Department of Neurology and Center for the Study of the Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri, U.S.A.
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  • Abbreviations used : BDNF, brain-derived neurotrophic factor ; EGF, epidermal growth factor ; ERK, extracellular-regulated protein kinase ; IGF 1, insulin-like growth factor 1 ; MBP, myelin basic protein ; MEK1, mitogen-activated protein kinase kinase ; NGF, nerve growth factor ; NT 3, neurotrophin 3 ; PBS, phosphate-buffered saline ; PKC, protein kinase C ; p-Tyr, phosphotyrosine ; Trk, tyrosine kinase.

Address correspondence and reprint requests to Dr. D. W. Choi at Department of Neurology, Box 8111, 660 South Euclid Avenue, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.

Abstract

Abstract : We report here that addition of the protein kinase C inhibitor Gö 6976 blocked neurotrophin-induced signaling and autophosphorylation of neurotrophin-specific tyrosine kinase (Trk) receptors, either Trk B in cortical neurons or Trk A in GT1-1-trk9 cells. The effect of Gö 6976 on Trk autophosphorylation was not inhibited by 100μM orthovanadate, suggesting that the block was not due to the activation of tyrosine phosphatases. Moreover, addition of 10-100 nM concentrations of Gö 6976 inhibited either Trk B or Trk A intrinsic kinase activity in cell-free assays. Gö 6976 also blocked the ability of brain-derived neurotrophic factor to promote cortical neuronal survival and the ability of nerve growth factor to promote PC12 cell survival and differentiation. These results suggest that Gö 6976, besides its known inhibitory effects on lipid- and calcium-dependent isoforms of protein kinase C, can also inhibit neurotrophin signaling by directly inhibiting the instrinsic Trk.

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