[PDF][PDF] βTrCP-and Rsk1/2-mediated degradation of BimEL inhibits apoptosis

E Dehan, F Bassermann, D Guardavaccaro… - Molecular cell, 2009 - cell.com
E Dehan, F Bassermann, D Guardavaccaro, G Vasiliver-Shamis, M Cohen, KN Lowes…
Molecular cell, 2009cell.com
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 …
Summary
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.
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