NF-κB inducing kinase: a key regulator in the immune system and in cancer

Abstract

NF-κB inducing kinase (NIK) is a kinase that activates the canonical and non-canonical NF-κB pathways to control transcriptional expression of certain proteins such as cytokines, chemokines and NF-κB signaling molecules. Many advances have been made in understanding the molecular mechanisms by which the stability of NIK is regulated to affect downstream signaling. Genetic mouse models suggest that NIK plays an essential role in the regulation of the immune system as well as in the bone microenvironment. Increasing evidence links NIK to the tumorigenesis of hematological cancers, such as multiple myeloma, and solid tumors, such as pancreatic carcinoma and melanoma. Understanding the mechanism by which NIK is de-regulated will potentially provide therapeutic options for certain diseases such as autoimmunity and cancer.

Figure 1

Figure 1A. At a basal level, NIK undergoes constant proteosomal degradation, executed by four E3 uibiquitin ligases, cIAP1/2 and TRAF2/3. Under such conditions, minimal signaling emanates from NIK. B. Upon ligand stimulation (for example, LTβR or CD40), there are two possible processes for activation of the non-canonical pathway: 1) E3 ubiquitin ligases such as TRAF2 and 3 are degraded, leading to stabilization of NIK; 2) when the receptor is activated, it competes for TRAF2/3, thus disassembling the degradative complex from NIK. As a result, NIK becomes stabilized to perform downstream functions, including stimulation of p100 proteolysis. When NIK is stabilized by inducers of the non-canonical NF-κB pathway, amplification of the canonical NF-κB pathway can occur, even though NIK is not required for this pathway.

Figure 2

Different domains of NIK interact with specific substrates and regulators, and are crucial for NIK function. The C-terminus of NIK mainly interacts with substrates such as IKK and p100, and NIK regulators, such as TRAF1, 2, 5 and 6. The N-terminus of NIK regulates the stability of the protein by interacting with TRAF3. So far, only one phosphorylation site (Thr-559) on NIK has been identified in its kinase domain. Aly mutation in the C-terminus impedes the function of NIK. NIK also has sequences for nuclear and nucleolar localization signals, which enable the protein to shuttle between different cellular compartments.

Figure 3

The function of NIK in inducing the proteolysis of p100 to p52 is required for osteoclastogenesis. The I B function of p100 deters NF-κB family members such as RelA and RelB to translocate to the nucleus. Re-expression of RelB rescues the defective osteoclastogenesis in osteoclast precursors but RelA does not, suggesting that only RelB is required for the osteoclastogenesis.