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

5 years ago

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.

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Wang et al. show site-specific phosphorylation-induced metabolic stabilization of Bcl3 through switch of ubiquitin linkage and transcriptional coregulatory activity of Bcl3 in association with NF-κB p50 and p52. Through identification of several Bcl3 kinases targeting specific sites, this work also establishes convergence of three intertwined signaling pathways onto NF-κB activation.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517304380