Bcl3 Phosphorylation by Akt, Erk2, and IKK Is Required for Its Transcriptional Activity.

Unlike prototypical IκB proteins, which are inhibitors of NF-κB RelA, cRel, and RelB dimers, the atypical IκB 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 IκB-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-κB through Bcl3 and provides mechanistic insight into how Bcl3 functions as an oncoprotein through collaboration with IKK1/2, Akt, and Erk2.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Cell Movement, Cell Proliferation, HEK293 Cells, HeLa Cells, Humans, I-kappa B Kinase, Mice, Mitogen-Activated Protein Kinase 1, Mutation, NF-kappa B p50 Subunit, NF-kappa B p52 Subunit, Phosphorylation, Protein Stability, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, RAW 264.7 Cells, RNA Interference, Serine, Signal Transduction, Transcription Factors, Transcription, Genetic, Transfection, Ubiquitination
Mol. Cell
Date: Aug. 03, 2017
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