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J. Biol. Chem., Vol. 277, Issue 51, 49473-49480, December 20, 2002
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From the 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.
K252a and CEP1347 Are Neuroprotective Compounds That Inhibit
Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK*
§,,¶,
,, and
Centre for Neuronal Survival, Montreal
Neurological Institute, McGill University, Montréal, Québec
H3A 2B4, Canada and ** Aegera Therapeutics Incorporated,
Montréal, Québec H3E 1A8, Canada
*
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 a National Cancer Institute of Canada studentship.
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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