Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function.
Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation.
Luciano
Frederic
F
INSERM Unit 526, LNC Label, Faculté de Médecine, 28 Avenue de Valombrose, 06107 Nice Cedex 02, France.
Jacquel
Arnaud
A
Colosetti
Pascal
P
Herrant
Magali
M
Cagnol
Sebastien
S
Pages
Gilles
G
Auberger
Patrick
P
D000595:Amino Acid Sequence; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008223:Lymphoma / Q000378:metabolism; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012694:Serine / Q000737:chemistry*; D013629:Tamoxifen / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D013629:Tamoxifen; D012694:Serine; D005982:Glutathione Transferase; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D013755:Tetradecanoylphorbol Acetate