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Mol. Cell. Biol. 32 (23): 4756-4768

Copyright © 2012 by the American Society for Microbiology. All rights reserved.

I{kappa}B Kinase {varepsilon} Phosphorylates TRAF2 To Promote Mammary Epithelial Cell Transformation

Rhine R. Shen,a,c Alicia Y. Zhou,a,c Eejung Kim,a,c Elgene Lim,a Hasem Habelhah,d, and William C. Hahna,b,c

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA,a Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA,b Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA,c Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA,d

Received for publication 6 April 2012. Revision received 24 May 2012. Accepted for publication 13 September 2012.

Abstract: NF-{kappa}B transcription factors are central regulators of inflammation and when dysregulated contribute to malignant transformation. I{kappa}B kinase {varepsilon} (IKK{varepsilon}; IKKi, encoded by IKBKE) is a breast oncogene that is amplified in 30% of breast cancers and drives transformation in an NF-{kappa}B-dependent manner. Here we demonstrate that IKK{varepsilon} interacts with and phosphorylates tumor necrosis factor receptor-associated factor 2 (TRAF2) at Ser11 in vitro and in vivo. This activity promotes Lys63-linked TRAF2 ubiquitination and NF-{kappa}B activation and is essential for IKK{varepsilon} transformation. Breast cancer cells that depend on IKK{varepsilon} expression for survival are also dependent on TRAF2. This work defines TRAF2 phosphorylation to be one key effector of IKK{varepsilon}-induced mammary epithelial cell transformation.


Address correspondence to William C. Hahn, William_Hahn{at}dfci.harvard.edu.

Published ahead of print 24 September 2012




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