|
Roux PP, Dorval G, Boudreau M, Angers-Loustau A, Morris SJ, Makkerh J, Barker
PA.
K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage
kinase-3 and induce activation of Akt and ERK.
J Biol Chem. 2002 Dec 20;277(51):49473-80. Epub 2002 Oct 17
Centre for Neuronal Survival, Montreal Neurological
Institute, McGill University, Montréal, Québec 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.
PMID: 12388555 |
