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

The BimEL tumor suppressor is a potent proapop- totic BH3-only protein. We found that, in response to survival signals, BimEL was rapidly phosphory- lated on three serine residues in a conserved degron, facilitating binding and degradation via the F box protein bTrCP. 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 phos- phorylation mutant unable to bind bTrCP was stabi- lized 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 rele- vant tyrosine kinase inhibitor that induces apoptosis through BimEL), silencing of either bTrCP or Rsk1/2 resulted in BimEL-mediated apoptosis of both gefiti- nib-sensitive and gefitinib-insensitive NSCLC cells. Our findings reveal that bTrCP promotes cell survival in cooperation with the ERK-RSK pathway by target- ing BimEL for degradation.