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 journalArticle

117 Citations (Scopus)

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
Externally publishedYes

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Phosphorylation
Apoptosis
Non-Small Cell Lung Carcinoma
F-Box Proteins
MAP Kinase Signaling System
Protein-Tyrosine Kinases
Serine
Cell Survival
gefitinib
Neoplasms
Proteins

Keywords

  • CELLCYCLE
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Dehan, E., Bassermann, F., Guardavaccaro, D., Vasiliver-Shamis, G., Cohen, M., Lowes, K. N., ... Pagano, M. (2009). βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis. Molecular Cell, 33(1), 109-116. https://doi.org/10.1016/j.molcel.2008.12.020

βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis. / Dehan, Elinor; Bassermann, Florian; Guardavaccaro, Daniele; Vasiliver-Shamis, Gaia; Cohen, Michael; Lowes, Kym N.; Dustin, Michael; Huang, David C S; Taunton, Jack; Pagano, Michele.

In: Molecular Cell, Vol. 33, No. 1, 16.01.2009, p. 109-116.

Research output: Contribution to journalArticle

Dehan, E, Bassermann, F, Guardavaccaro, D, Vasiliver-Shamis, G, Cohen, M, Lowes, KN, Dustin, M, Huang, DCS, Taunton, J & Pagano, M 2009, 'βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis', Molecular Cell, vol. 33, no. 1, pp. 109-116. https://doi.org/10.1016/j.molcel.2008.12.020
Dehan E, Bassermann F, Guardavaccaro D, Vasiliver-Shamis G, Cohen M, Lowes KN et al. βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis. Molecular Cell. 2009 Jan 16;33(1):109-116. https://doi.org/10.1016/j.molcel.2008.12.020
Dehan, Elinor ; Bassermann, Florian ; Guardavaccaro, Daniele ; Vasiliver-Shamis, Gaia ; Cohen, Michael ; Lowes, Kym N. ; Dustin, Michael ; Huang, David C S ; Taunton, Jack ; Pagano, Michele. / βTrCP- and Rsk1/2-Mediated Degradation of BimEL Inhibits Apoptosis. In: Molecular Cell. 2009 ; Vol. 33, No. 1. pp. 109-116.
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