betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis.

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.
Mesh Terms:
Animals, Apoptosis, Apoptosis Regulatory Proteins, Cell Line, Humans, Membrane Proteins, Mice, Protein Processing, Post-Translational, Protein Stability, Proto-Oncogene Proteins, Ribosomal Protein S6 Kinases, 90-kDa, beta-Transducin Repeat-Containing Proteins
Mol. Cell
Date: Jan. 16, 2009
Download Curated Data For This Publication
144532
Switch View:
  • Interactions 8