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

• Published in: Cell death and differentiation Vol. 19; no. 4; pp. 633 - 641
• Main Authors: Sandow, J J, Jabbour, A M, Condina, M R, Daunt, C P, Stomski, F C, Green, B D, Riffkin, C D, Hoffmann, P, Guthridge, M A, Silke, J, Lopez, A F, Ekert, P G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2012; Nature Publishing Group
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Cell Death - physiology; Cell Line; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Interleukin-3 - genetics; Interleukin-3 - metabolism; Life Sciences; Mice; Mice, Knockout; NF-kappa B - genetics; NF-kappa B - metabolism; Original Paper; Phosphorylation - physiology; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Protein Processing, Post-Translational - physiology; Proteolysis; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptors, Interleukin-3 - genetics; Receptors, Interleukin-3 - metabolism; Signal Transduction - physiology; Stem Cells; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; IKK; interleukin-3; degradation; PUMA; phosphorylation; post-translational
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/cdd.2011.131

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 NF κ B signaling. The identification and characterization of this novel survival pathway has important implications for IL-3 signaling and hematopoietic cell development.