β-TrCP binding and processing of NF-κB2/p100 involve its phosphorylation at serines 866 and 870

Liang, Chunyang; Zhang, Minying; Sun, Shao Cong

doi:10.1016/j.cellsig.2005.10.011

Cited by 92 publications

(99 citation statements)

References 40 publications

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“…NIK induces the binding of βTrCP to p100, which is dependent on the two conserved serine phosphorylation residues, serines 866 and 870 ( Figure 2). In vitro binding assays using phospho-peptides further confirmed that phosphorylation of the conserved serine residues within the phoshorylation site of p100 creates a binding site for βTrCP [16]. Consistent with these findings, βTrCP knockdown by RNAi attenuates NIKinduced p100 ubiquitination and processing, thus establishing SCF βTrCP as a ubiquitin ligase mediating the inducible processing of p100 [15].…”

Section: Regulation By Ubiquitinationsupporting

confidence: 68%

“…Initial in vitro kinase assays, using NIK immune complexes isolated from transfected HEK 293 cells, identified these two serines as potential phosphorylation sites of p100 [5]. This finding was later on confirmed by immunoblotting assays using phospho-specific anti-p100 antibodies [16]. In both NIK-transfected 293 cells and signal-induced B cells and fibroblasts, the serines 860 and 870 of endogenous p100 are strongly phosphorylated.…”

Section: Regulation By Site-specific P100 Phosphorylationmentioning

confidence: 79%

“…NIK gene mutation in the alymphoplasia (aly) or NIK knockout mice, however, has no obvious effect on TNFα-stimulated NF-κB activation, but completely blocks the processing of p100 [5,35,36]. Consistently, NIK stimulates the phosphorylation, ubiquitination, and processing of p100 in transfected cells [5,16]. To date, all of the non-canonical NF-κB inducers identified so far are known to signal through NIK [7,[11][12][13][14].…”

Section: Nik and Ikkα As Key Non-canonical Nf-κb Signaling Componentsmentioning

confidence: 79%

“…This region of p100 contains two serine residues, S866 and S870, which resemble the phosphorylation site of IκBα [15]. Mutation of one or both of these serines completely abolished the inducible processing of p100 [5,16]. Initial in vitro kinase assays, using NIK immune complexes isolated from transfected HEK 293 cells, identified these two serines as potential phosphorylation sites of p100 [5].…”

Section: Regulation By Site-specific P100 Phosphorylationmentioning

confidence: 99%

“…In both NIK-transfected 293 cells and signal-induced B cells and fibroblasts, the serines 860 and 870 of endogenous p100 are strongly phosphorylated. As seen with the induction of p100 processing [11,17], the signal-induced p100 phosphorylation is dependent on de novo protein synthesis [16], and the potential underlying mechanism will be discussed in a following section.…”

Section: Regulation By Site-specific P100 Phosphorylationmentioning

confidence: 99%

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Non-canonical NF-κB signaling pathway

2010

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The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

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Section: Regulation By Ubiquitinationsupporting

confidence: 68%

Section: Regulation By Site-specific P100 Phosphorylationmentioning

confidence: 79%

Section: Nik and Ikkα As Key Non-canonical Nf-κb Signaling Componentsmentioning

confidence: 79%

Section: Regulation By Site-specific P100 Phosphorylationmentioning

confidence: 99%

Section: Regulation By Site-specific P100 Phosphorylationmentioning

confidence: 99%

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Non-canonical NF-κB signaling pathway

2010

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TRIM14 Promotes Noncanonical NF‐κB Activation by Modulating p100/p52 Stability via Selective Autophagy

et al. 2019

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The noncanonical NF‐κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF‐κB signaling largely relies on the abundance as well as the processing of the NF‐κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF‐κB signaling pathway. TRIM14 promotes noncanonical NF‐κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63‐linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62‐mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF‐κB‐mediated inflammatory responses as well as acute colitis and colitis‐associated colon cancer development. Taken together, these findings establish the TRIM14‐USP14 axis as a crucial checkpoint that controls noncanonical NF‐κB signaling and highlight the crosstalk between autophagy and innate immunity.

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NF‐κB signaling in inflammation and cancer

Zhang

et al. 2021

MedComm

188

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Since nuclear factor of κ‐light chain of enhancer‐activated B cells (NF‐κB) was discovered in 1986, extraordinary efforts have been made to understand the function and regulating mechanism of NF‐κB for 35 years, which lead to significant progress. Meanwhile, the molecular mechanisms regulating NF‐κB activation have also been illuminated, the cascades of signaling events leading to NF‐κB activity and key components of the NF‐κB pathway are also identified. It has been suggested NF‐κB plays an important role in human diseases, especially inflammation‐related diseases. These studies make the NF‐κB an attractive target for disease treatment. This review aims to summarize the knowledge of the family members of NF‐κB, as well as the basic mechanisms of NF‐κB signaling pathway activation. We will also review the effects of dysregulated NF‐κB on inflammation, tumorigenesis, and tumor microenvironment. The progression of the translational study and drug development targeting NF‐κB for inflammatory diseases and cancer treatment and the potential obstacles will be discussed. Further investigations on the precise functions of NF‐κB in the physiological and pathological settings and underlying mechanisms are in the urgent need to develop drugs targeting NF‐κB for inflammatory diseases and cancer treatment, with minimal side effects.

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β-TrCP binding and processing of NF-κB2/p100 involve its phosphorylation at serines 866 and 870

Cited by 92 publications

References 40 publications

Non-canonical NF-κB signaling pathway

Non-canonical NF-κB signaling pathway

TRIM14 Promotes Noncanonical NF‐κB Activation by Modulating p100/p52 Stability via Selective Autophagy

NF‐κB signaling in inflammation and cancer

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