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Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity.

The "BH3-only" proapoptotic BCL-2 family members initiate the intrinsic apoptotic pathway. A small interfering RNA knockdown of BIM confirms this BH3-only member is important for the cytokine-mediated homeostasis of hematopoietic cells. We show here that the phosphorylation status of BIM controls its proapoptotic activity. IL-3, a hematopoietic survival factor, induces extracellular signal-regulated kinase/mitogen-activated protein kinase-mediated phosphorylation of BIM on three serine sites (S55, S65, and S100). After IL-3 withdrawal, only nonphosphorylated BIM interacts with the multidomain proapoptotic effector BAX. Phosphorylation of BIM on exposure of cells to IL-3 dramatically reduces the BIM/BAX interaction. A nonphosphorylatable BIM molecule (S55A, S65A, and S100A) demonstrates enhanced interaction with BAX and enhanced proapoptotic activity. Thus, ERK/mitogen-activated protein kinase-dependent phosphorylation of BIM in response to survival factor regulates BIM/BAX interaction and the pro-death activity of BIM.

Pubmed ID: 15486085


  • Harada H
  • Quearry B
  • Ruiz-Vela A
  • Korsmeyer SJ


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 26, 2004

Associated Grants


Mesh Terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Extracellular Signal-Regulated MAP Kinases
  • Membrane Proteins
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein