K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK

• Published in: The Journal of biological chemistry Vol. 277; no. 51; pp. 49473 - 49480
• Main Authors: Roux, Philippe P., Dorval, Geneviève, Boudreau, Mathieu, Angers-Loustau, Alexandre, Morris, Stephen J., Makkerh, Joe, Barker, Philip A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.12.2002; American Society for Biochemistry and Molecular Biology
• Subjects: Adenoviridae - genetics; Animals; Carbazoles - pharmacology; Cell Line; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors - pharmacology; Indole Alkaloids; Indoles - pharmacology; Inhibitory Concentration 50; MAP Kinase Kinase Kinases - antagonists & inhibitors; Mice; Mitogen-Activated Protein Kinase Kinase Kinase 11; Mitogen-Activated Protein Kinases - metabolism; Models, Chemical; Neurons - cytology; Neurons - metabolism; Neuroprotective Agents - pharmacology; PC12 Cells; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Precipitin Tests; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Recombinant Proteins - metabolism; Signal Transduction; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M203428200

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.