Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

NF-kappa B-Inducing Kinase (NIK)

  • Robert P. NelsonEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_110-1



One of the many kinases which transduce signals from the cell membrane to the nucleus in select cells and processes.


Using TRAF2 to study proteins involved in NFKB pathways, Malinin et al. cloned NK-kappa B inducing kinase (NIK) (Malinin et al. 1997). NIK, which is a multifunctional, is officially known as mitogen-activated protein-kinase-kinase-kinase 14 (MAP 3K14) participates in the activation of NF-kB by TNF, CD95, IL1, but not TGF beta, which uses an NIK-independent mechanisms. (Sakurai et al. 1998) The “canonical” NF-kB pathway drives many inflammatory processes; however, the “noncanonical” pathway is also a crucial activation cascade (Zarnegar et al. 2008). The NIK-dependent pathway is “noncanonical,” in that it does not require the NF-kappa essential modulator (NEMO, inhibitor of nuclear factor kappa-B kinase subunit gamma) (Gray et al. 2014)....

This is a preview of subscription content, log in to check access.


  1. Awane M, Andres PG, Li DJ, Reinecker HC. NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol. 1999;162:5337–44.PubMedGoogle Scholar
  2. Aya K, Alhawagri M, Hagen-Stapleton A, Kitaura H, Kanagawa O, Novack DV. NF-(kappa)B-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis. J Clin Invest. 2005;115:1848–54.CrossRefGoogle Scholar
  3. Gray CM, Remouchamps C, McCorkell KA, et al. Noncanonical NF-kappaB signaling is limited by classical NF-kappaB activity. Sci Signal. 2014;7:ra13.CrossRefGoogle Scholar
  4. Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, Vartanian T. The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome. J Biol Chem. 2001;276:8865–74.CrossRefGoogle Scholar
  5. Kajiura F, Sun S, Nomura T, et al. NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol. 2004;172:2067–75.CrossRefGoogle Scholar
  6. Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997;385(6616):540–4.CrossRefGoogle Scholar
  7. Matsumoto M, Yamada T, Yoshinaga SK, et al. Essential role of NF-kappa B-inducing kinase in T cell activation through the TCR/CD3 pathway. J Immunol. 2002;169:1151–8.CrossRefGoogle Scholar
  8. Pan Q, Kravchenko V, Katz A, et al. NF-kappa B-inducing kinase regulates selected gene expression in the Nod2 signaling pathway. Infect Immun. 2006;74:2121–7.CrossRefGoogle Scholar
  9. Sakurai H, Shigemori N, Hasegawa K, Sugita T. TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism. Biochem Biophys Res Commun. 1998;243:545–9.CrossRefGoogle Scholar
  10. Schlechter N, Glanzmann B, Hoal EG, Schoeman M, Petersen BS, Franke A, Lau YL, et al. Exome sequencing identifies a novel MAP3K14 mutation in recessive atypical combined immunodeficiency. Front Immunol. 2017;8:1624.CrossRefGoogle Scholar
  11. Shinkura R, Kitada K, Matsuda F, et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet. 1999;22:74–7.CrossRefGoogle Scholar
  12. Willmann KL, Klaver S, Dogu F, et al. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Nat Commun. 2014;5:5360.CrossRefGoogle Scholar
  13. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997;278:866–9.CrossRefGoogle Scholar
  14. Yamada T, Mitani T, Yorita K, et al. Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kappa B-inducing kinase. J Immunol. 2000;165:804–12.CrossRefGoogle Scholar
  15. Yang J, Zhang S, Zhang L, et al. Lymphatic endothelial cells regulate B-cell homing to lymph nodes via a NIK-dependent mechanism. Cell Mol Immunol. 2019;16:165–77.CrossRefGoogle Scholar
  16. Zarnegar BJ, Wang Y, Mahoney DJ, et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008;9:1371–8.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Professor of Medicine and PediatricsIndiana University School of Medicine, Immunohematology and TransplantationIndianapolisUSA

Section editors and affiliations

  • M Teresa de la Morena
    • 1
  • Robert P. Nelson
    • 2
  1. 1.University of Washington and Seattle Children's HospitalSeattleUSA
  2. 2.Hematology and OncologyIndiana UniversityIndianapolisUSA