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

Molecular Cell
Elinor DehanMichele Pagano

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 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.

References

Feb 28, 1998·The EMBO Journal·L O'ConnorD C Huang
Aug 10, 2000·The American Journal of Pathology·L A O'ReillyA Strasser
Apr 14, 2004·Proceedings of the National Academy of Sciences of the United States of America·Alexander EgleSuzanne Cory
Nov 23, 2005·The Journal of Cell Biology·Nisrine El ChamiDaniel C Régnier
Sep 9, 2006·Blood·Cinta Mestre-EscorihuelaJose A Martinez-Climent
Sep 26, 2006·Proceedings of the National Academy of Sciences of the United States of America·Junya KurodaAndreas Strasser
Oct 17, 2006·The Biochemical Journal·Gopal P SapkotaDario R Alessi
Sep 22, 2007·Cellular Signalling·Ceri M WigginsSimon J Cook
Jan 17, 2008·Cell Cycle·Jamie I Fletcher, David C S Huang
Apr 19, 2008·The Journal of Biological Chemistry·Weizhou ZhangLu-Hai Wang
May 9, 2008·Molecular & Cellular Proteomics : MCP·Yu XueXuebiao Yao
May 24, 2008·Molecular Cell·Anette HübnerRoger J Davis
May 27, 2008·Nature Reviews. Cancer·David Frescas, Michele Pagano
Sep 25, 2008·Nature Reviews. Molecular Cell Biology·Rana Anjum, John Blenis

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Citations

Jun 3, 2011·Archivum Immunologiae Et Therapiae Experimentalis·Toru Akiyama, Sakae Tanaka
Aug 21, 2013·Trends in Cell Biology·Kaleigh Fernald, Manabu Kurokawa
Jan 20, 2012·Cell Death & Disease·Y Shao, A E Aplin
Jun 24, 2011·Nature Reviews. Molecular Cell Biology·Domagoj VucicIngrid E Wertz
May 26, 2011·Science Signaling·Huei-Chi WenJulio A Aguirre-Ghiso
Mar 28, 2013·Science Signaling·Gregory R BeanEmily H-Y Cheng
Apr 14, 2010·Molecular and Cellular Biology·Daniel P StewartJoseph T Opferman
Apr 24, 2013·Molecular and Cellular Biology·Lingtao JinSumin Kang
Jul 23, 2011·Genes & Cancer·Teresa A SoucyJames E Brownell
Aug 4, 2012·Critical Reviews in Eukaryotic Gene Expression·Hisashi Harada, Steven Grant
May 13, 2014·Cells·Barbara MojsaSolange Desagher
Feb 23, 2013·ISRN Hematology·Ronit Vogt Sionov
Oct 26, 2010·Expert Opinion on Therapeutic Targets·Sumin Kang, Jing Chen
Jun 6, 2014·Annals of Medicine·Nicole M KettnerLoning Fu
Jan 23, 2016·Journal of Translational Medicine·Noufira PoomakkothFatima Mraiche
Apr 9, 2011·EMBO Reports·Scott E Millman, Michele Pagano
Mar 13, 2013·EMBO Reports·Franziska ErtelGordon C Shore
Oct 3, 2015·Seminars in Cancer Biology·Yuan Liu, Rama K Mallampalli
Mar 26, 2015·Frontiers in Genetics·Kerstin BrinkmannHamid Kashkar
Dec 18, 2014·Science Signaling·Teck Yew LowAlbert J R Heck
Aug 16, 2016·Cellular & Molecular Immunology·Jie LiCui Hua Liu
Feb 15, 2011·Cancer Cell·Ian R WatsonMichael Ohh
Sep 25, 2009·Current Opinion in Cell Biology·Jeffrey R Skaar, Michele Pagano
Jul 3, 2009·Current Opinion in Cell Biology·Andrew P GilmoreJennefer Lindsay
Nov 15, 2014·Nature Reviews. Drug Discovery·Jeffrey R SkaarMichele Pagano

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