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Multisite phosphorylation regulates Bim stability and apoptotic activity.

The proapoptotic BH3-only protein Bim is established to be an important mediator of signaling pathways that induce cell death. Multisite phosphorylation of Bim by several members of the MAP kinase group is implicated as a regulatory mechanism that controls the apoptotic activity of Bim. To test the role of Bim phosphorylation in vivo, we constructed mice with a series of mutant alleles that express phosphorylation-defective Bim proteins. We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival. In contrast, mutation of the phosphorylation sites Ser-55, Ser-65, and Ser-73 can cause increased apoptosis because of reduced proteasomal degradation of Bim. Together, these data indicate that phosphorylation can regulate Bim by multiple mechanisms and that the phosphorylation of Bim on different sites can contribute to the sensitivity of cellular apoptotic responses.

Pubmed ID: 18498746


  • Hübner A
  • Barrett T
  • Flavell RA
  • Davis RJ


Molecular cell

Publication Data

May 23, 2008

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK52530
  • Agency: NCI NIH HHS, Id: R01 CA065861
  • Agency: NCI NIH HHS, Id: R01 CA065861-13
  • Agency: NINDS NIH HHS, Id: R01 NS054948
  • Agency: NINDS NIH HHS, Id: R01 NS054948-03
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Cells, Cultured
  • Fibroblasts
  • Humans
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases
  • Phosphorylation
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Signal Transduction
  • Thymus Gland