Bcl3 Phosphorylation by Akt, Erk2, and IKK Is Required for Its Transcriptional Activity.
Mol Cell
; 67(3): 484-497.e5, 2017 Aug 03.
Article
em En
| MEDLINE
| ID: mdl-28689659
ABSTRACT
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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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Transcrição Gênica
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Proteínas Proto-Oncogênicas
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Proteína Quinase 1 Ativada por Mitógeno
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Quinase I-kappa B
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Proteínas Proto-Oncogênicas c-akt
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article