Multisite phosphorylation regulates Bim stability and apoptotic activity
Howard Hughes Medical Institute; Program in Molecular Medicine
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
Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
Mol Cell. 2008 May 23;30(4):415-25. Link to article on publisher's site
Hubner, Anette; Barrett, Tamera; Flavell, Richard A.; and Davis, Roger J., "Multisite phosphorylation regulates Bim stability and apoptotic activity" (2008). Open Access Articles. 1949.