Trends in Biochemical Sciences
Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation
Section snippets
Three NF-κB-activating pathways
Three distinct NF-κB-activating pathways have emerged, and all of them rely on sequentially activated kinases (Figure 1). The first pathway –the classical pathway – is triggered by pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and leads to the sequential recruitment of various adaptors including TNF-receptor-associated death domain protein (TRADD), receptor-interacting protein (RIP) and TNF-receptor-associated factor 2 (TRAF2) to the cytoplasmic membrane [3]. This is
Phosphorylations of other IκB proteins
All these reports convincingly demonstrate that phosphorylation of IκB proteins such as IκBα and p100 is essential for NF-κB activation. The inhibitory molecule IκBβ is also targeted for phosphorylation on Ser19 and Ser23 by the IKK complex [24] and this phosphorylation triggers IκBβ degradation – similar to IKK-mediated IκBε phosphorylation of N-terminal serine residues [25].
The ankyrin-containing and inhibitory molecule p105 is also subjected to TNFα and IKK-mediated phosphorylation on Ser927
Optimal NF-κB activation by phosphorylation of p65
Besides the phosphorylation and subsequent degradation of inhibitory molecules, protein kinases are also required for optimal NF-κB activation by targeting functional domains of NF-κB proteins themselves. These additional pathways explain why cells lacking kinases such as GSK3β and TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1; also named T2K or NAK) have defects in NF-κB activation despite an unaltered profile of IκBα phosphorylation and degradation in response to TNFα 34, 35.
The crucial role of phosphorylation in the regulation of RelB and c-Rel activity
Multiple residues of the NF-κB protein RelB are phosphorylated. Ser368 seems to be essential for RelB dimerization and p100 stabilization, but not for RelB nuclear import [60]. However, the kinase that targets this site has not been identified. Phosphorylation of RelB at Thr84 and Ser552 in cells stimulated by 12-O-tetradecanoylphorbol 13-acetate and ionomycin triggers degradation of RelB via the proteasome pathway but, again, the identity of the kinase that phosphorylates RelB at these
p50 and p52 NF-κB subunits are phosphoproteins
Although much has been reported regarding the phosphorylation of p65, and to a lesser extend RelB and c-Rel, there is little information about the phosphorylation of other NF-κB proteins, despite the fact that it has been known for many years that members of the NF-κB family (e.g. p50) are phosphorylated upon cell stimulation [68]. Because p50 lacks a transactivating domain, protein phosphorylation regulates its DNA-binding properties. Indeed, PKA-mediated phosphorylation at Ser337, which is
Implications of NF-κB and IκB phosphorylation in inflammation and cancer
Because NF-κB is activated by pro-inflammatory cytokines, induces cell proliferation and anti-apoptotic gene expression, and also enhances angiogenesis via vascular endothelial growth factor expression, it is not surprising that aberrant NF-κB activity is a hallmark of cancer and chronic inflammatory diseases. Altered NF-κB activation is caused by deregulated, and often constitutive, NF-κB and IκB phosphorylations, which are major contributors to these diseases. Indeed, constitutive IKK
Future directions
Although many phosphorylation sites on NF-κB proteins have been characterized, it is still unclear how these phosphorylations regulate the ability of such proteins to induce or to repress defined target genes. The answers might come from the use of knock-in experiments in which a mouse expressing mutant NF-κB proteins that lack key phosphorylation sites is generated. Phenotypic analysis of these mice would provide a powerful biological model to address the regulation of NF-κB protein activities
Acknowledgements
A.C. and M-P.M. are Research Associates at the Belgian National Funds for Research. A.C. is supported by a grant from the Belgian Federation against Cancer and TELEVIE. The members of the laboratory are also supported by grants from the Belgian Funds for Research (FNRS) and the Centre anti-cancéreux. We thank E. Dejardin for helpful discussions.
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