Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis.
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.
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Esther B E
EB
Becker
Jenny
J
Howell
Yuki
Y
Kodama
Philip A
PA
Barker
Azad
A
Bonni
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012694:Serine / Q000378:metabolism
D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D012694:Serine; D048031:JNK Mitogen-Activated Protein Kinases; C498884:c-jun N-terminal kinase Bim(EL), rat; D048728:MAP Kinase Kinase Kinase 1