Abstract
K-252b, a member of the staurosporine family of protein kinase inhibitors, selectively potentiates the activation of the nerve growth factor receptor, TrkA, by a nonpreferred ligand, neurotrophin-3 (NT-3), in a variety of cell types. At higher (micromolar) concentrations of K-252b, an inhibitory effect occurs because of the inhibitory action of K-252b on the Trk kinase. By examining analogs of K-252b, we identified the compound L-753,000 (NB-506), which potentiates the action of NT-3 on TrkA but is devoid of the inhibitory action of K-252b. L-753,000 was effective at nanomolar concentrations in a Chinese hamster ovary cell line that expressed TrkA but was devoid of p75, the low-affinity neurotrophin receptor. L-753,000 also potentiated the activation of mitogen-activating protein kinase signaling (downstream from Trk activation) by NT-3 in this cell line. Although L-753,000, like K-252b, had a negligible effect in the absence of NT-3, the compound was found to potentiate NT-3-induced survival in both rat and chick primary cultures of dissociated dorsal root ganglia (DRG) and on neurite outgrowth of chick DRG explants. Unlike K-252b, which at micromolar concentrations inhibits the survival response of NT-3 in dissociated rat DRG, L-753,000 continued to potentiate the actions of NT-3 up to a concentration of 10 μM. Furthermore, the compound, unlike K-252b, did not inhibit an unrelated protein kinase, protein kinase C, at concentrations up to 10 μM. Because L-753,000 selectively potentiates the NT-3-induced stimulation of TrkA without inhibiting Trks and other protein kinases, it represents a novel class of selective modifiers of neurotrophin actions.
Footnotes
- Received December 18, 1998.
- Accepted April 12, 1999.
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Send reprint requests to: Dr. Scott Pollack, Department of Biochemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK. E-mail: scott_pollack{at}merck.com
- The American Society for Pharmacology and Experimental Therapeutics
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