title: IκB kinase ε phosphorylates TRAF2 to promote mammary epithelial cell transformation.
abstract: NF-κB transcription factors are central regulators of inflammation and when dysregulated contribute to malignant transformation. IκB kinase ε (IKKε; IKKi, encoded by IKBKE) is a breast oncogene that is amplified in 30% of breast cancers and drives transformation in an NF-κB-dependent manner. Here we demonstrate that IKKε 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-κB activation and is essential for IKKε transformation. Breast cancer cells that depend on IKKε expression for survival are also dependent on TRAF2. This work defines TRAF2 phosphorylation to be one key effector of IKKε-induced mammary epithelial cell transformation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Rhine R
authors.initials: RR
authors.lastname: Shen
authors.forename: Alicia Y
authors.initials: AY
authors.lastname: Zhou
authors.forename: Eejung
authors.initials: E
authors.lastname: Kim
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.forename: Hasem
authors.initials: H
authors.lastname: Habelhah
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001940:Breast / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D041681:NIH 3T3 Cells; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C119724:AGFG1 protein, human; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D047992:TNF Receptor-Associated Factor 2; D051550:I-kappa B Kinase; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases