beta TrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis
- Author(s)
- Dehan, E; Bassermann, F; Guardavaccaro, D; Vasiliver-Shamis, G; Cohen, M; Lowes, KN; Dustin, M; Huang, DCS; Taunton, J; Pagano, M;
- Details
- Publication Year 2009-01-16,Volume 33,Issue #1,Page 109-116
- Journal Title
- MOLECULAR CELL
- Publication Type
- Journal Article
- 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 beta TrCP. 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 beta TrCP 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 tyrosine kinase inhibitor that induces apoptosis through BimEL), silencing of either beta TrCP or Rsk1/2 resulted in BimEL-mediated apoptosis of both gefitinib-sensitive and gefitinib-insensitive NSCLC cells. Our findings reveal that beta TrCP promotes cell survival in cooperation with the ERK-RSK pathway by targeting BimEL for degradation.
- Publisher
- CELL PRESS
- Keywords
- BH3-ONLY PROTEIN BIM(EL); REGULATED KINASES 1/2; BCL-2 FAMILY; HOMOZYGOUS DELETIONS; GERM-CELLS; PHOSPHORYLATION; PROMOTES; IDENTIFICATION; SUPPRESSOR; TURNOVER
- Publisher's Version
- https://doi.org/10.1016/j.molcel.2008.12.020
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2009-01-16 12:00:00