Cytokine receptor signaling activates an IKK-dependent phosphorylation of PUMA to prevent cell death

J J Sandow, Anissa Jabbour, M R Condina, Carmel Daunt, Frank Stomski, Benjamin Green, C Riffkin, Peter Hoffmann, Mark Guthridge, John Silke, A F Lopez, Paul Ekert

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27 Citations (Scopus)


P53-upregulated modifier of apoptosis (PUMA), a pro-apoptotic member of the Bcl-2 family, is transcriptionally activated by p53 and is a key effector of p53-dependent apoptosis. We show that PUMA protein is subject to rapid post-translational regulation by phosphorylation at a conserved residue, serine 10, following serum or interleukin-3 (IL-3) stimulation. Serine 10 is not within the Bcl-2 homology (BH3) domain, and PUMA phosphorylated at serine 10 retained the ability to co-immunoprecipitate with antiapoptotic Bcl-2 family members. However, phosphorylated PUMA was targeted for proteasomal degradation indicating that it is less stable than unphosphorylated PUMA. Importantly, we identified IKK1/IKK2/Nemo as the kinase complex that interacts with and phosphorylates PUMA, thereby also demonstrating that IL-3 activates NFB signaling. The identification and characterization of this novel survival pathway has important implications for IL-3 signaling and hematopoietic cell development. A? 2012 Macmillan Publishers Limited All rights reserved.
Original languageEnglish
Pages (from-to)633 - 641
Number of pages9
JournalCell Death and Differentiation
Issue number4
Publication statusPublished - 2012

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