Journal article
βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis
E Dehan, F Bassermann, D Guardavaccaro, G Vasiliver-Shamis, M Cohen, KN Lowes, M Dustin, DCS Huang, J Taunton, M Pagano
Molecular Cell | Published : 2009
Abstract
The BimEL tumor suppressor is a potent proapoptotic BH3-only protein. We found that, in response to survival signals, BimEL was rapidly phosphorylated on three serine residues in a conserved degron, facilitating binding and degradation via the F box protein βTrCP. Phosphorylation of the BimEL degron was executed by Rsk1/2 and promoted by the Erk1/2-mediated phosphorylation of BimEL on Ser69. Compared to wild-type BimEL, a BimEL phosphorylation mutant unable to bind βTrCP was stabilized and consequently potent at inducing apoptosis by the intrinsic mitochondrial pathway. Moreover, although non-small cell lung cancer (NSCLC) cells often become resistant to gefitinib (a clinically relevant tyro..
View full abstractGrants
Awarded by National Institutes of Health
Funding Acknowledgements
We thank M. McMahon, D. Ryoo, and J. Skaar for suggestions and for critically reading the manuscript; E. McIntush and Bethyl Laboratories for providing beta TrCP1 (BL726b) antibody; and I. Aifantis, J. Blenis, P. Bouillet, S. Buonamici, T. Cardozo, C. Lee, S. Fuchs, K. Kinnally, S. Korsmeyer L. Liebes, J. Maller, W. Pao, S. Valvo, and H.G. Wang for reagents and/or suggestions. M.P. is grateful to T.M. Thor for continuous support. This work was supported by a Department of Defense fellowship to E.D.; an American Association for Cancer Research (AACR) fellowship to F.B.; a fellowship from the America Italian Cancer Foundation and from Provincia di Benevento to D.G.; grants from the National Institutes of Health to M.P. (R01-GM57587, R37-CA76584, and R21-CA125173, M.L.D. (R01-A143542), and J.T. (GM071434); and an Australian National Health and Medical Research Council (NHMRC) Fellowship, an Australian NHMRC Program Grant, and a Leukemia and Lymphoma Society Specialized Center of Research (SCOR) grant (to D.C.S.H.). J.T. and M.P. are investigators with the Howard Hughes Medical Institute.