βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis

Elinor Dehan, Florian Bassermann, Daniele Guardavaccaro, Gaia Vasiliver-Shamis, Michael Cohen, Kym N. Lowes, Michael Dustin, David C.S. Huang, Jack Taunton, Michele Pagano

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

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 tyrosine kinase inhibitor that induces apoptosis through BimEL), silencing of either βTrCP or Rsk1/2 resulted in BimEL-mediated apoptosis of both gefitinib-sensitive and gefitinib-insensitive NSCLC cells. Our findings reveal that βTrCP promotes cell survival in cooperation with the ERK-RSK pathway by targeting BimEL for degradation.

Original languageEnglish (US)
Pages (from-to)109-116
Number of pages8
JournalMolecular Cell
Volume33
Issue number1
DOIs
StatePublished - Jan 16 2009

Keywords

  • CELLCYCLE
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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