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

ABSTRACT: Unlike prototypical I?B proteins, which are inhibitors of NF-?B RelA, cRel, and RelB dimers, the atypical I?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?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-?B through Bcl3 and provides mechanistic insight into how Bcl3 functions as an oncoprotein through collaboration with IKK1/2, Akt, and Erk2.

SUBMITTER: Wang VY 

PROVIDER: S-EPMC6571149 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature