期刊
MOLECULAR CELL
卷 67, 期 3, 页码 484-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2017.06.011
关键词
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资金
- Science and Technology Development Fund, Macao S.A.R. (FDCT) [023/2016/A1]
- National Institutes of Health [085490, 071862]
- [AI064326]
Unlike prototypical I kappa B proteins, which are inhibitors of NF-kappa B RelA, cRel, and RelB dimers, the atypical I kappa B protein Bcl3 is primarily a transcriptional coregulator of p52 and p50 homodimers. Bcl3 exists as phospho-protein in many cancer cells. Unphosphorylated Bcl3 acts as a classical I kappa B-like inhibitor and removes p50 and p52 from bound DNA. Neither the phosphorylation site(s) nor the kinase(s) phosphorylating Bcl3 is known. Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. Cells expressing the S114A/S446A mutant have cellular proliferation and migration defects. This work links Akt and MAPK pathways to NF-kappa B through Bcl3 and provides mechanistic insight into how Bcl3 functions as an oncoprotein through collaboration with IKK1/2, Akt, and Erk2.
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