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Originally published In Press as doi:10.1074/jbc.M203428200 on October 17, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49473-49480, December 20, 2002
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K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK*

Philippe P. RouxDagger §, Geneviève DorvalDagger , Mathieu BoudreauDagger , Alexandre Angers-LoustauDagger ||, Stephen J. Morris**, Joe MakkerhDagger , and Philip A. BarkerDagger Dagger Dagger

From the Dagger  Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montréal, Québec H3A 2B4, Canada and ** Aegera Therapeutics Incorporated, Montréal, Québec H3E 1A8, Canada

K252a is best known as a Trk inhibitor, but is also a neuroprotective compound. CEP1347, a K252a derivative, retains neuroprotective properties, but does not inhibit TrkA. CEP1347 has recently been shown to directly inhibit MAPKKKs, including MLK3, but the effect of K252a on MAPKKKs remains unknown. K252a and CEP1347 not only prevent death, but also facilitate neurite outgrowth and maintenance, somal hypertrophy, and neurotransmitter synthesis. The biochemical basis for these trophic effects remains unknown. We have compared the effects of CEP1347 and K252a on MLK and JNK signaling and on neurotrophic pathways that support survival and growth. Our data show that K252a is a potent inhibitor of MLK3 activity in vivo and in vitro (IC50 ~ 5 nM). However, we also found that K252a and CEP1347 activate Akt and ERK and show that blockade of phosphatidylinositol 3-kinase or MEK activity ablates the effect of K252a and CEP1347 on cell survival. Activation of Akt and ERK occurs through an MLK-independent pathway that may involve c-Src. Together, these data show that the neuroprotective and neurotrophic effects of K252a and CEP1347 involve activation of several neurotrophic signaling pathways.

* This work was supported in part by grants from the Canadian Institutes of Health Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a Canadian Institutes of Health Research studentship. Present address: Dept. of Cell Biology, Harvard Medical School, LHRRB, Boston, MA 02115.

Supported a Fonds de la Recherche en Santé des Quebecs studentship.

|| Supported a National Cancer Institute of Canada studentship.

Dagger Dagger To whom correspondence should be addressed: Montreal Neurological Inst., McGill University, 3801 University St., Montreal, Quebec H3A 2B4, Canada. Tel.: 514-398-3064; Fax: 514-398-5214; E-mail: phil.barker@mcgill.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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