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.
Dehan
Elinor
E
Department of Pathology, NYU Cancer Institute, Smilow Research Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Bassermann
Florian
F
Guardavaccaro
Daniele
D
Vasiliver-Shamis
Gaia
G
Cohen
Michael
M
Lowes
Kym N
KN
Dustin
Michael
M
Huang
David C S
DC
Taunton
Jack
J
Pagano
Michele
M
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3