Induction of p100 Processing by NF-κB-inducing Kinase Involves Docking IκB Kinase α (IKKα) to p100 and IKKα-mediated Phosphorylation*

By G. Xiao, A. Fong, Shao-Cong Sun. Journal of Biological Chemistry, 2004

271 citations recorded by the source corpus.

The processing of the nfκb2 gene product p100 to generate p52 is a regulated event, which is important for the instrumental function of NF-κB. We previously demonstrated that this tightly controlled event is regulated positively by NF-κB-inducing kinase (NIK) and its downstream kinase, IκB kinase α (IKKα). However, the precise mechanisms by which NIK and IKKα induce p100 processing remain unclear. Here, we show that, besides activating IKKα, NIK also serves as a docking molecule recruiting IKKα to p100. This novel function of NIK requires two specific amino acid residues, serine 866 and serine 870, of p100 that are known to be essential for inducible processing of p100. We also show that, after being recruited into p100 complex, activated IKKα phosphorylates specific serines located in both N- and C-terminal regions of p100 (serines 99, 108, 115, 123, and 872). The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100 mediated by the β-TrCP ubiquitin ligase and 26 S proteasome, respectively. These results highlight the critical but different roles of NIK and IKKα in regulating p100 processing and shed light on the mechanisms mediating the tight control of p100 processing. These data also provide the first evidence for explaining why overexpression of IKKα or its activation by many other stimuli such as tumor necrosis factor and mitogens fails to induce p100 processing.

Subfields: Cancer Research, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/7675db86a928668af5857f45b24219b0131cf1c1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

In Pathology and Forensic Medicine

Citations in the corpus

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway (2006, background): “The non-canonical NF-kB pathway involves the activation of NIK and IKKa with the subsequent phosphorylation of p100 within its C-terminal domain at Ser-866 and Ser-870 (Senftleben et al., 2001; Xiao et al., 2001; Bonizzi and Karin, 2004) (Figure 3; Table 3).”
TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. (2005, background): “Activated IKK , in turn, phosphorylates the NF- B p100 protein and induces its processing to the mature p52 subunit (Xiao et al. 2004).”