JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis

Neuron. 2003 Jun 19;38(6):899-914. doi: 10.1016/s0896-6273(03)00355-6.

Abstract

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

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Bcl-2-Like Protein 11
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Cerebellum
  • Enzyme Activation
  • Gene Expression Regulation
  • Immune Sera / pharmacology
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Membrane Proteins*
  • Mice
  • Mitochondria / enzymology
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Molecular Sequence Data
  • Mutagenesis
  • Nerve Growth Factor / immunology
  • Nerve Growth Factor / physiology
  • Neurons / physiology*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2*
  • Rats
  • Serine / genetics
  • Signal Transduction
  • Structure-Activity Relationship
  • Superior Cervical Ganglion
  • Transfection
  • bcl-2-Associated X Protein

Substances

  • Apoptosis Regulatory Proteins
  • Bax protein, mouse
  • Bax protein, rat
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bcl2l11 protein, rat
  • Carrier Proteins
  • Immune Sera
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Serine
  • Nerve Growth Factor
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases