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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.

Original publication

DOI

10.1016/j.molcel.2008.12.020

Type

Journal article

Journal

Molecular cell

Publication Date

01/2009

Volume

33

Pages

109 - 116

Addresses

Department of Pathology, NYU Cancer Institute, Smilow Research Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.

Keywords

Cell Line, Animals, Humans, Mice, Ribosomal Protein S6 Kinases, 90-kDa, beta-Transducin Repeat-Containing Proteins, Membrane Proteins, Proto-Oncogene Proteins, Apoptosis, Protein Processing, Post-Translational, Apoptosis Regulatory Proteins, Protein Stability, Bcl-2-Like Protein 11