TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105

@article{Belich1999TPL2KR,
  title={TPL-2 kinase regulates the proteolysis of the NF-$\kappa$B-inhibitory protein NF-$\kappa$B1 p105},
  author={M{\^o}nica P. Belich and Andres Salmeron and Leland H. Johnston and Steven C. Ley},
  journal={Nature},
  year={1999},
  volume={397},
  pages={363-368}
}
The transcription factor NF-κB is composed of homodimeric andheterodimeric complexes of Rel/NF-κB-family polypeptides, which include Rel-A, c-Rel, Rel-B, NF-κB1/p50 and NF-κB2/p52 (ref. 1). The NF-κB1 gene encodes a larger precursor protein, p105, from which p50 is produced constitutively by proteasome-mediated removal of the p105 carboxy terminus. The p105 precursor also acts as an NFκB-inhibitory protein, retaining associated p50, c-Rel and Rel-A proteins in the cytoplasm through its carboxy… 
βTrCP-Mediated Proteolysis of NF-κB1 p105 Requires Phosphorylation of p105 Serines 927 and 932
TLDR
It appears that reduced p105 recruitment of βTrCP and subsequent ubiquitination may contribute to delayed p105 proteolysis after TNF-α stimulation relative to that for IκBα.
Direct Phosphorylation of NF-κB1 p105 by the IκB Kinase Complex on Serine 927 Is Essential for Signal-induced p105 Proteolysis*
TLDR
Together these experiments indicate that the IKK complex regulates the signal-induced proteolysis of NF-κB1 p105 by direct phosphorylation of serine 927 in its PEST domain.
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TLDR
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Shared Pathways of IκB Kinase-Induced SCFβTrCP-Mediated Ubiquitination and Degradation for the NF-κB Precursor p105 and IκBα
TLDR
It is shown here that IKKβ phosphorylation of p105 is direct and does not require kinases downstream of IKK, and a functional endogenous IKK complex is required for signal-induced p105 degradation but not for processing.
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TLDR
P105 functions as a regulator of MAP kinase signalling, in addition to its role in NF-κB activation, after stimulation with agonists, which releases associated p50, which translocates into the nucleus to modulate target gene expression.
Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase
TLDR
This review summarizes the current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of T PL-2 in immune and inflammatory responses.
The Death Domain of NF-κB1 p105 Is Essential for Signal-induced p105 Proteolysis*
TLDR
The p105 DD acts as a docking site for IKK, increasing its local concentration in the vicinity of the p105 PEST region and facilitating efficient serine 927 phosphorylation.
NF-κ B p 105 is a target of I κ B kinases and controls signal induction of Bcl-3 – p 50 complexes
TLDR
It is suggested that the known NF-κB stimuli not only cause nuclear accumulation of p50–p65 heterodimers but also of Bcl-3–p50 and perhaps further transcription activator complexes which are formed upon IKK-mediated p105 degradation.
The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling
TLDR
There is strong biochemical and genetic evidence that the IKK complex, which consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, Ikkγ, is the master regulator of NF-κB-mediated innate immune and inflammatory responses.
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TLDR
It is demonstrated that the p105 and p98 precursors share functional properties with the I kappa B proteins, which also contain SWI6/ankyrin repeats, suggesting a second pathway leading to NF-kappa B induction, in which processing of the precursor rather than phosphorylation of I k Kappa B plays a major role.
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TLDR
Investigation of the posttranslational regulation of p105 following activation of Jurkat T cells finds that a rapid and sustained phosphorylation of p 105 is induced, and regulates that of IκBα, involving inducible serine phosphorylated and proteolysis of the inhibitory ankyrin repeat domain, it depends on a different, redox-insensitive, signaling pathway.
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TLDR
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TLDR
It is reported here that a 23-amino-acid, glycine-rich region (GRR) in p105 functions as a processing signal for the generation of p50, and it is demonstrated that the GRR can direct a similar processing event when it is inserted into a protein unrelated to the NF-kappaB family and that it is therefore an independent signal for processing.
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TLDR
It is demonstrated that, following stimulation of human monocytic cells with lipopolysaccharide or tumor necrosis factor-α, this critical p105 processing event is up-regulated in concert with the inactivation of IκBα, providing direct biochemical evidence that p105 and IκBs are differentially sensitive targets for inducible proteolysis via ATP-dependent degradative pathways.
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TLDR
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