3 years ago

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

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.

Graphical abstract



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

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