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Unformatted text preview: K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK* Received for publication, April 9, 2002, and in revised form, September 20, 2002 Published, JBC Papers in Press, October 17, 2002, DOI 10.1074/jbc.M203428200 Philippe P. Roux, Genevie `ve Dorval, Mathieu Boudreau , Alexandre Angers-Loustau , Stephen J. Morris**, Joe Makkerh, and Philip A. Barker From the Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montre al, Que bec H3A 2B4, Canada and ** Aegera Therapeutics Incorporated, Montre al, Que bec H3E 1A8, Canada K252a is best known as a Trk inhibitor, but is also a neuroprotective compound. CEP1347, a K252a deriva- tive, retains neuroprotective properties, but does not inhibit TrkA. CEP1347 has recently been shown to di- rectly inhibit MAPKKKs, including MLK3, but the effect of K252a on MAPKKKs remains unknown. K252a and CEP1347 not only prevent death, but also facilitate neu- rite 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 sup- port survival and growth. Our data show that K252a is a potent inhibitor of MLK3 activity in vivo and in vitro (IC 50 5 n M ). 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. Acti- vation of Akt and ERK occurs through an MLK-inde- pendent pathway that may involve c-Src. Together, these data show that the neuroprotective and neurotro- phic effects of K252a and CEP1347 involve activation of several neurotrophic signaling pathways. Cell death plays a crucial role during neuronal development, but in the adult, apoptotic cascades can contribute to neurode- generative disease (15). The precise signaling mechanisms that induce neuronal apoptotic cascades are not yet certain, but key findings have emerged from analysis of nerve growth factor (NGF) 1-dependent sympathetic neurons subjected to neurotro- phin withdrawal. In this system, NGF deprivation results in activation of Rac and Cdc42 and their association with mito- gen-activated protein kinase kinase kinases (MAPKKKs), in- cluding the mixed-lineage kinases (MLKs) (68). Activation of these MAPKKKs initiates a stress kinase cascade that leads to activation of c-Jun N-terminal kinase (JNK), which then phos- phorylates and activates c-Jun. c-Jun-dependent transcription results in Bak/Bax-dependent release of cytochrome c from mitochondria and the activation of caspase-9 (9, 10)....
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