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 has an essential role in 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. KeywordsNF-κB inducing kinase (NIK); NF-κB; IKK; canonical pathway; non-canonical pathwayThe nuclear factor-κB (NF-κB) family of transcription factors is comprised of a collection of structurally related proteins that modulate multiple physiological processes, ranging from immune responses to cell death and survival. These transcription factors are ubiquitously expressed and control the expression of a significant number of genes. Multiple kinases and signaling molecules are responsible for the precise regulation of the NF-κB pathway, one of which is NF-κB inducing kinase (NIK). In this review, we will discuss the function and regulation of NIK in relation to its role in the NF-κB pathway, as well as some functions of NIK that are independent of the NF-κB pathway. We will also review the functional significance of NIK in the context of physiological processes such as immune regulation, and in disease models such as autoimmunity and cancer. NIK in the regulation of NF-κB NIK as a kinase of the canonical and non-canonical NF-κB pathwaysThe family of NF-κB in mammals is comprised of five members; p65 (RelA), p105/p50, RelB, p100/p52 and c-Rel. Regulation of NF-κB can be achieved by two distinct pathways.

Induction of the Alternative NF-κB Pathway by Lymphotoxin αβ (LTαβ) Relies on Internalization of LTβ Receptor

“…Interestingly, ligand-dependent or -independent LT␤R internalization might be linked to cancer progression. Indeed, we showed that dynamin-dependent internalization of LT␤R is required for NIK stabilization, and exacerbated accumulation of NIK has been reported in hematopoietic as well as nonhematopoietic cancer cells (50). For instance, liver-specific LT␣/LT␤ expression leads to hepatitis-induced hepatocellular carcinoma development and this phenotype can be reversed when mice are treated with Fc-LT␤R recombinant decoy receptors (18).…”

NIK Controls Classical and Alternative NF-κB Activation and Is Necessary for the Survival of Human T-cell Lymphoma Cells

“…In some cases, genetic alterations such as gene amplifications, translocations, or mutations in NIK, or alterations in genes regulating the stability of NIK protein, are described, emphasizing the role of NIK in tumorigenesis (14,19,34). From previous reports, the role of NIK in the alternative NF-kB pathway is clear, but the involvement of NIK in the regulation of the classical pathway seems to be signal and cell type dependent (13,35). For example, in melanoma and pancreatic cancer, NIK only affects the alternative pathway (22,36), whereas NIK regulates both pathways in DLBCL and multiple myeloma (14,16).…”

Chemokines in cancer related inflammation

“…In melanoma, constitutive activation of NF-κB is responsible for CXCL1 production [20,21] and in acute myelogenous leukemia high levels of the transcription factor MEF2C induce over-expression of CCL2, CCL3 and CCL4 [22]. CXCR4 and CCR5 can also be transactivated by the Insulin-like Growth Factor-1 or via its receptor [23,24].…”