9: J Biol Chem. 2002 Dec 20;277(51):49473-80. Epub 2002 Oct 17.
K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage
kinase-3 and induce activation of Akt and ERK.
Roux PP, Dorval G, Boudreau M, Angers-Loustau A, Morris SJ, Makkerh J, Barker
PA.
Centre for Neuronal Survival, Montreal Neurological Institute, McGill
University, Montreal, Quebec H3A 2B4, 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 (IC(50) approximately 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.
Publication Types:
Research Support, Non-U.S. Gov't
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