Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function.

Frederic Luciano (1) , Arnaud Jacquel (1) , Pascal Colosetti (1) , Magali Herrant (1) , Sebastien Cagnol (2) , Gilles Pages (2) , Patrick Auberger (1)

1 Physiopathologie de la survie et de la mort cellulaire et infection virale
2 ISBDC - Institut de signalisation, biologie du développement et cancer

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.

Domaines: Biologie moléculaire; Cancer

Frederic Luciano, Arnaud Jacquel, Pascal Colosetti, Magali Herrant, Sebastien Cagnol, et al.. Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function.. Oncogene, 2003, 22 (43), pp.6785-93. ⟨10.1038/sj.onc.1206792⟩. ⟨hal-00323924⟩