Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis

Esther B.E. Becker, Jenny Howell, Yuki Kodama, Philip A. Barker, Azad Bonni

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

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 Bim EL 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.

Original languageEnglish
Pages (from-to)8762-8770
Number of pages9
JournalJournal of Neuroscience
Volume24
Issue number40
DOIs
StatePublished - Oct 6 2004

Keywords

  • Apoptosis
  • BH3-only
  • Neuron
  • Protein kinase
  • Signal transduction
  • Survival
  • p75 neurotrophin receptor

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