JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis

Trophic factor deprivation (TFD) activates c-Jun N-terminal kinases (JNKs), culminating in coordinate AP1- dependent transactivation of the BH3-only BCL-2 proteins BIMEL and HRK, which in turn are critical for BAX-dependent cytochrome c release, caspase activation, and apoptosis. Here, we report that TFD caused not only induction but also phosphorylation of BIMEL. Mitochondrially localized JNKs but not upstream activators, like mixed-lineage kinases (MLKs) or mitogen-activated protein kinase kinases (MKKs), specifically phosphorylated BIMEL at Ser65, potentiating its proapoptotic activity. Inhibition of the JNK pathway attenuated BIMEL expression, prevented BIMEL phosphorylation, and abrogated TFD-induced apoptosis. Conversely, activation of this pathway promoted BIMEL expression and phosphorylation, causing BIM- and BAX-dependent cell death. Thus, JNKs regulate the proapoptotic activity of BIMEL during TFD, both transcriptionally and posttranslationally.