Phosphorylation of bim-el by erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function

ABSTRACT 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. Access through your institution Buy or

subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 50 print issues and online

access $259.00 per year only $5.18 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which

are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS

TRIM15 AND CYLD REGULATE ERK ACTIVATION VIA LYSINE-63-LINKED POLYUBIQUITINATION Article 08 September 2021 PHOSPHATASE PP2A ENHANCES MCL-1 PROTEIN HALF-LIFE IN MULTIPLE MYELOMA CELLS Article

Open access 03 March 2021 MITOCHONDRIAL E3 UBIQUITIN LIGASE MARCHF5 CONTROLS BAK APOPTOTIC ACTIVITY INDEPENDENTLY OF BH3-ONLY PROTEINS Article 28 September 2022 REFERENCES * Bertolotto C,

Maulon L, Filippa N, Baier G and Auberger P . (2000). _J. Biol. Chem._, 275, 37246–37250. * Biswas SC and Greene LA . (2002). _J. Biol. Chem._, 277, 49511–49516. * Bonni A, Brunet A, West

AE, Datta SR, Takasu MA and Greenberg ME . (1999). _Science_, 286, 1358–1362. * Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM and Strasser A . (1999). _Science_,

286, 1735–1738. * Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM and Strasser A . (2002). _Nature_, 415, 922–926. * Breitschopf K,

Haendeler J, Malchow P, Zeiher AM and Dimmeler S . (2000). _Mol. Cell. Biol._, 20, 1886–1896. * Brichese L, Barboule N, Heliez C and Valette A . (2002). _Exp. Cell. Res._, 278, 101–111. *

Cory S and Adams JM . (2002). _Nat. Rev. Cancer_, 2, 647–656. * Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME . (1997). _Cell_, 91, 231–241. * Dimmeler S, Breitschopf

K, Haendeler J and Zeiher AM . (1999). _J. Exp. Med._, 189, 1815–1822. * Lei K and Davis RJ . (2003). _Proc. Natl. Acad. Sci. USA_, 100, 2432–2437. * Luciano F, Ricci JE and Auberger P .

(2001). _Oncogene_, 20, 4935–4941. * Luciano F, Ricci JE, Herrant M, Bertolotto C, Mari B, Cousin JL and Auberger P . (2002). _Leukemia_, 16, 700–707. * Meier P and Evan G . (1998). _Cell_,

95, 295–298. * O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S and Huang DC . (1998). _EMBO J._, 17, 384–395. * Pages G, Guerin S, Grall D, Bonino F, Smith A,

Anjuere F, Auberger P and Pouyssegur J . (1999). _Science_, 286, 1374–1377. * Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A and Johnson EM . (2001). _Neuron_, 29,

615–628. * Puthalakath H, Huang DC, O'Reilly LA, King SM and Strasser A . (1999). _Mol. Cell_, 3, 287–296. * Puthalakath H and Strasser A . (2002). _Cell Death Differ._, 9, 505–512. *

Ricci JE, Lang V, Luciano F, Belhacene N, Giordanengo V, Michel F, Bismuth G and Auberger P . (2001a). _Faseb J._, 15, 1777–1779. * Ricci JE, Maulon L, Battaglione-Hofman V, Bertolotto C,

Luciano F, Mari B, Hofman P and Auberger P . (2001b). _Eur. Cytokine Netw._, 12, 126–134. * Shinjyo T, Kuribara R, Inukai T, Hosoi H, Kinoshita T, Miyajima A, Houghton PJ, Look AT, Ozawa K

and Inaba T . (2001). _Mol. Cell. Biol._, 21, 854–864. * Smith DB and Johnson KS . (1988). _Gene_, 67, 31–40. * Weston CR, Balmanno K, Chalmers C, Hadfield K, Molton SA, Ley R, Wagner EF and

Cook SJ . (2003). _Oncogene_, 22, 1281–1293. * Xia Z, Dickens M, Raingeaud J, Davis RJ and Greenberg ME . (1995). _Science_, 270, 1326. * Zha J, Harada H, Yang E, Jockel J and Korsmeyer SJ

. (1996). _Cell_, 87, 619–628. Download references ACKNOWLEDGEMENTS This work was supported by INSERM, The Ligue Nationale contre le Cancer (LNC, Equipe labellisée). We are undebted to Dr

David Huang and Dr Andreas Strasser (WEHI, Melbourne, Australia) for the kind gift of Bim constructs. FL is a fellowship from the LNC. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * INSERM

Unit 526, LNC Label, Faculté de Médecine, 28 Avenue de Valombrose, Nice, Cedex 02, 06107, France Frederic Luciano, Arnaud Jacquel, Pascal Colosetti, Magali Herrant, Sebastien Cagnol & 

Patrick Auberger * UMR CNRS 6547, Centre Antoine Lacassagne, Avenue de valombrose, Nice, Cedex 02, 06100, France Gilles Pages Authors * Frederic Luciano View author publications You can also

search for this author inPubMed Google Scholar * Arnaud Jacquel View author publications You can also search for this author inPubMed Google Scholar * Pascal Colosetti View author

publications You can also search for this author inPubMed Google Scholar * Magali Herrant View author publications You can also search for this author inPubMed Google Scholar * Sebastien

Cagnol View author publications You can also search for this author inPubMed Google Scholar * Gilles Pages View author publications You can also search for this author inPubMed Google

Scholar * Patrick Auberger View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Patrick Auberger. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Luciano, F., Jacquel, A., Colosetti, P. _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_ 22, 6785–6793 (2003). https://doi.org/10.1038/sj.onc.1206792 Download citation * Received: 10 April

2003 * Revised: 19 May 2003 * Accepted: 19 May 2003 * Published: 02 October 2003 * Issue Date: 02 October 2003 * DOI: https://doi.org/10.1038/sj.onc.1206792 SHARE THIS ARTICLE Anyone you

share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the

Springer Nature SharedIt content-sharing initiative KEYWORDS * Bim * Erk1/2 * proteasome * apoptosis