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The Journal of Neuroscience, October 6, 2004, 24(40):8762-8770; doi:10.1523/JNEUROSCI.2953-04.2004

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Cellular/Molecular
Characterization of the c-Jun N-Terminal Kinase-BimEL Signaling Pathway in Neuronal Apoptosis

Esther B. E. Becker,1,2 Jenny Howell,3 Yuki Kodama,1 Philip A. Barker,3 and Azad Bonni1,2

1Department of Pathology and 2Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, and 3Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada

The c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in mediating apoptosis in the nervous system; however, the mechanisms by which JNK triggers neuronal apoptosis remain incompletely understood. Recent studies suggest that in addition to inducing transcription of pro-apoptotic genes, JNK also directly activates the cell death machinery. Here, we report that JNK catalyzed the phosphorylation of the BH3-only protein Bcl-2 interacting mediator of cell death (BimEL) at serine 65, both in vitro and in vivo. The JNK-induced phosphorylation of BimEL at serine 65 promoted the apoptotic effect of BimEL in primary cerebellar granule neurons. We also characterized the role of the JNK-BimEL signaling pathway in apoptosis that was triggered by overexpression of the p75 neurotrophin receptor (p75NTR). We found that activation of p75NTR induced the JNK-dependent phosphorylation of endogenous BimEL at serine 65 in cells. The genetic knockdown of BimEL by RNA interference or the expression of a dominant interfering form of BimEL significantly impaired the ability of activated p75NTR to induce apoptosis. Together, these results suggest that JNK-induced phosphorylation of BimEL at serine 65 mediates p75NTR-induced apoptosis. Our findings define a novel mechanism by which a death-receptor pathway directly activates the mitochondrial apoptotic machinery.

Key words: apoptosis; survival; neuron; BH3-only; signal transduction; p75 neurotrophin receptor; protein kinase

Received Oct 15, 2003; revised August 24, 2004; accepted August 26, 2004.




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