Phosphorylation Study of IkB Protein Bcl3

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	Phosphorylation Study of IkB Protein Bcl3
	Wang, V. Y.-F.; Meshcheryakov, V.; Li, Y.; Ghosh, G.
	2019-10-07
Source Publication	Abstract of papers at the 2019 Cold Spring Harbor Asia Conference on NF-kB, JAK-STAT and MAPK in Health, Disease & Therapy
Abstract	B cell leukemia/lymphoma 3 (Bcl3) was identified as an oncoprotein in a subgroup of B cell lymphocytic leukemias with t (14;19) chromosomal translocation. In subsequent studies Bcl3 locus translocation was identified in other types of hematological malignancy. In these cancer cells, Bcl3 is expressed at 3-4 fold higher levels than wild type cells. In many solid tumors, Bcl3 is overexpressed without undergoing chromosomal alterations suggesting other mechanisms for its activation. Bcl3 is shown to play a decisive role in promoting cell migration by activating genes that facilitate cell migration and suppressing genes that inhibit cell death. While excessive Bcl3 is oncogenic, the lack of Bcl3 severely compromises immunity. Bcl3 is a member of the inhibitor of NF-B (IB) family, which forms stable complexes with NF-B transcription factors. IB proteins contain three structural regions. The central region contains six to seven ankyrin repeats (AR) that fold into the ankyrin repeat domain (ARD). The ARD provides the primary contacting surface for NF-B binding. Classical IB proteins (IB, - and -) prefer RelA or cRel containing NF-B dimers. In contrast, Bcl3 prefers NF-B p52 or p50 homodimers. Apart from the nuclear localization sequence (NLS), the N-terminus of Bcl3 is structurally featureless; the serine and proline rich C-terminus is apparently flexible. Bcl3 exists as a phospho-protein in many cancer cells. Unphosphorylated Bcl3 acts as classical IB-like inhibitor, which removes p50 and p52 from bound DNA in vitro. Neither the phosphorylation site(s) nor the kinase(s) phosphorylating Bcl3 are known. Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of the ubiquitination linkage from K48 to K63. This phosphorylation thus promotes nuclear localization and stabilization of Bcl3 from continuous degradation. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 in the flexible N- and C-terminal segments converts Bcl3 into a transcriptional coregulator of p50 and p52 by facilitating its recruitment to B DNA. Cells expressing Bcl3 S114A/S446A double mutant cannot function as a transcriptional coregulator resulting in cellular proliferation and migration defects. This work directly links Akt and MAPK pathways to NF-B through Bcl3 and provides mechanistic insight into how Bcl3 might function as an oncoprotein through collaboration with IKK1/2, Akt, and Erk2.
Keyword	Phosphorylation NFkB IkB Bcl3
Language	英語English
The Source to Article	PB_Publication
PUB ID	49197
Document Type	Conference paper
Collection	DEPARTMENT OF BIOMEDICAL SCIENCES
Corresponding Author	Wang, V. Y.-F.
Recommended Citation GB/T 7714	Wang, V. Y.-F.,Meshcheryakov, V.,Li, Y.,et al. Phosphorylation Study of IkB Protein Bcl3[C], 2019.
APA	Wang, V. Y.-F.., Meshcheryakov, V.., Li, Y.., & Ghosh, G. (2019). Phosphorylation Study of IkB Protein Bcl3. Abstract of papers at the 2019 Cold Spring Harbor Asia Conference on NF-kB, JAK-STAT and MAPK in Health, Disease & Therapy.

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