βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis
| Autor: | Kym N Lowes, Gaia Vasiliver-Shamis, Michele Pagano, Florian Bassermann, David C.S. Huang, Michael L. Dustin, Michael B. Cohen, Jack Taunton, Daniele Guardavaccaro, Elinor Dehan |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Beta-Transducin Repeat-Containing Proteins
Apoptosis Ribosomal Protein S6 Kinases 90-kDa Article Cell Line ubiquitin apoptosis ligase Mice Ubiquitin Proto-Oncogene Proteins ubiquitin Animals Humans Gene silencing Molecular Biology apoptosis ligase Bcl-2-Like Protein 11 biology Protein Stability Bcl-2 family Membrane Proteins Cell Biology Cell cycle beta-Transducin Repeat-Containing Proteins Cell biology respiratory tract diseases biology.protein Phosphorylation Degron Apoptosis Regulatory Proteins Protein Processing Post-Translational |
| Zdroj: | Molecular Cell. 33(1):109-116 |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2008.12.020 |
| Popis: | 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 betaTrCP. 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 betaTrCP 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 betaTrCP or Rsk1/2 resulted in BimEL-mediated apoptosis of both gefitinib-sensitive and gefitinib-insensitive NSCLC cells. Our findings reveal that betaTrCP promotes cell survival in cooperation with the ERK-RSK pathway by targeting BimEL for degradation. |
| Databáze: | OpenAIRE |
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