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Gene Review

MAP3K14  -  mitogen-activated protein kinase kinase...

Homo sapiens

Synonyms: FTDCR1B, HS, HSNIK, HsNIK, Mitogen-activated protein kinase kinase kinase 14, ...
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Disease relevance of MAP3K14


High impact information on MAP3K14

  • Our genetic evidence confirms that p100 is required and sufficient as a fourth IkappaB protein for noncanonical NF-kappaB signaling downstream of NIK and IKK1 [6].
  • This phosphorylation of IkappaB-alpha is greatly enhanced by NIK costimulation [7].
  • This latter component is a new protein, termed IKK-complex-associated protein (IKAP), which can bind NIK and IKKs and assemble them into an active kinase complex [8].
  • Our findings indicate that NIK participates in an NF-kappaB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor [9].
  • IKK-alpha and IKK-beta formed heterodimers that interacted with NIK [10].

Chemical compound and disease context of MAP3K14


Biological context of MAP3K14

  • Moreover, whereas IFN promotes cell survival in lymphoblastoid cells, expression of dominant negative NIK and TRAF2 constructs enhances IFN-induced apoptosis [12].
  • Using various truncation mutants of NIK, we identified a functional nuclear export signal within the COOH-terminal region 795-805, which counteracts the inherent NLS at amino acids 143-149 [13].
  • CONCLUSION: During the initial state of HBV infection, hepatocytes facilitate the activation of NF-kappaB through up regulation of LT-alpha, TRAF2, and NIK [14].
  • NF-kappaB activation was also inhibited by transfection of kinase-deficient NIK or a dominant negative mutant of upstream adapter protein TRAF2 or TRAF6 [15].
  • IL-1beta induced H2O2 production in MCF-7 cells and clearance of this ROS through the expression of GPx-1 reduced NFkappaB transcriptional activation by inhibiting NIK-mediated phosphorylation of IKKalpha [16].

Anatomical context of MAP3K14

  • In both 293 cells and primary splenic B cells, the ability of CD40 to trigger p100 processing requires functional NF-kappaB-inducing kinase (NIK) [17].
  • In vivo, NIK enhances immune responses against a vector-encoded antigen and shifts them toward a T helper 1 immune response with increased IgG2a levels, T cell proliferation, IFN-gamma production, and cytotoxic T lymphocyte responses more potently than complete Freund's adjuvant, a very efficacious T helper 1-inducing adjuvant [18].
  • The introduction of kinase-inactive IKKalpha, activation loop mutants of IKKalpha, or IKKalpha antisense RNA into 293 or HeLa cells blocks NIK (NF-kappaB-inducing kinase)-induced phosphorylation of the IKKbeta activation loop occurring in functional signalsomes [19].
  • Second, triggering of this pathway by StpC in both T lymphoid and epithelial cells is dependent on the presence of functional NF-kappaB-inducing kinase (NIK) [20].
  • In this study, we have isolated a mouse cDNA encoding a protein kinase homologous to Nck-interacting kinase (NIK), a member of the group I germinal center kinase family [21].

Associations of MAP3K14 with chemical compounds

  • However, after addition of leptomycin B, NIK rapidly accumulated in the nucleus, whereas we could not detect any significant effect on TRAF2 or IKK2 [13].
  • A mutant form of IKK-alpha containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-kappaB activation [22].
  • Tumor necrosis factor receptor-activated factor 6 (TRAF6) and the nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK) are both involved in subsequent steps of NF-kappaB activation [23].
  • In vitro assays show that NIK interacts directly with ERM proteins, binding their N termini and phosphorylating a conserved C-terminal threonine [24].
  • In this report we demonstrate that both NIK and IkappaB kinase alpha (IKKalpha) are involved in LTbetaR signaling and that the phosphorylation of the p65 subunit at serine 536 in its transactivation domain 1 (TA1) plays an essential role [25].

Physical interactions of MAP3K14

  • Herein we show that NIK interacts with additional members of the TRAF family and that this interaction requires the conserved "WKI" motif within the TRAF domain [26].
  • NFkappaB-inducing kinase (NIK) is upstream of the IkappaB kinase complex that induces IkappaBalpha degradation [27].

Regulatory relationships of MAP3K14

  • NIK cannot phosphorylate IkappaB-alpha directly, but it appears to be a functionally important subunit, because mutated NIK inhibited stimulus-induced kappaB-dependent transcription more effectively than mutated IKK-alpha or -beta [28].
  • Taken together, our data implicate involvement of I kappa B kinase and MAPK signaling cascades in NIK-induced constitutive activation of NF-kappa B [3].
  • A NIK kinase inactive mutant could block ErbB2/ErbB4 and EGF-induced NF-kappaB activation [29].
  • The IkappaB kinases (IKKs) lie downstream of the NF-kappaB-inducing kinase (NIK) and activate NF-kappaB by phosphorylation of IkappaBalpha [30].
  • Taken together, these results demonstrate that H2O2 induces the IL-6 promoter by activating NFkappaB through NIK [27].

Other interactions of MAP3K14

  • The NF-kappaB-inducing kinase (NIK) associates with TRAF2 and mediates TNF activation of NF-kappaB [26].
  • Whereas overexpression of NIK potently induced NF-kappaB activation, it failed to stimulate JNK activation [26].
  • We conclude that NF-kappaB.IkappaB complexes and the upstream signaling kinases NIK and IKK1 shuttle between cytoplasm and nucleus of nonactivated cells and that this process leads to a basal transcriptional activity of NF-kappaB [13].
  • These data suggest that TNAP is a repressor of NIK activity and regulates both the classical and alternative NF-kappaB signaling pathways [31].
  • Using a dominant negative NIK mutant, we show that NIK activation is required for EGFR-mediated NF-kappaB induction [32].

Analytical, diagnostic and therapeutic context of MAP3K14

  • Thus, production of reactive oxygen species, aspirin (asp)-sensitive enzymes of the arachidonate metabolism, and NIK are common transducers of AII- and TNF-dependent pathways to NFkappaB [33].
  • Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade [34].
  • Although 5-FU did not affect the expression levels of IKKs, NIK, or MEKK-1, IKK activity in cl-1 cells was suppressed at both 6 h and 12 h after treatment with 2 microgram/ml 5-FU [35].
  • A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin [36].
  • Immunoprecipitation kinase assays indicate that NIK kinase activity is activated even more rapidly (within 6 h of RSV adsorption) associated with an endogenous approximately 50-kDa NF-kappaB2 substrate [2].


  1. Induction of proinflammatory mediators requires activation of the TRAF, NIK, IKK and NF-kappaB signal transduction pathway in astrocytes infected with Escherichia coli. Kim, J.M., Oh, Y.K., Lee, J.H., Im, D.Y., Kim, Y.J., Youn, J., Lee, C.H., Son, H., Lee, Y.S., Park, J.Y., Choi, I.H. Clin. Exp. Immunol. (2005) [Pubmed]
  2. Respiratory syncytial virus influences NF-kappaB-dependent gene expression through a novel pathway involving MAP3K14/NIK expression and nuclear complex formation with NF-kappaB2. Choudhary, S., Boldogh, S., Garofalo, R., Jamaluddin, M., Brasier, A.R. J. Virol. (2005) [Pubmed]
  3. A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. Dhawan, P., Richmond, A. J. Biol. Chem. (2002) [Pubmed]
  4. The NIK protein kinase and C17orf1 genes: chromosomal mapping, gene structures and mutational screening in frontotemporal dementia and parkinsonism linked to chromosome 17. Aronsson, F.C., Magnusson, P., Andersson, B., Karsten, S.L., Shibasaki, Y., Lendon, C.L., Goate, A.M., Brookes, A.J. Hum. Genet. (1998) [Pubmed]
  5. Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Suh, J., Payvandi, F., Edelstein, L.C., Amenta, P.S., Zong, W.X., Gélinas, C., Rabson, A.B. Prostate (2002) [Pubmed]
  6. A Fourth IkappaB Protein within the NF-kappaB Signaling Module. Basak, S., Kim, H., Kearns, J.D., Tergaonkar, V., O'dea, E., Werner, S.L., Benedict, C.A., Ware, C.F., Ghosh, G., Verma, I.M., Hoffmann, A. Cell (2007) [Pubmed]
  7. Identification and characterization of an IkappaB kinase. Régnier, C.H., Song, H.Y., Gao, X., Goeddel, D.V., Cao, Z., Rothe, M. Cell (1997) [Pubmed]
  8. IKAP is a scaffold protein of the IkappaB kinase complex. Cohen, L., Henzel, W.J., Baeuerle, P.A. Nature (1998) [Pubmed]
  9. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Malinin, N.L., Boldin, M.P., Kovalenko, A.V., Wallach, D. Nature (1997) [Pubmed]
  10. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Woronicz, J.D., Gao, X., Cao, Z., Rothe, M., Goeddel, D.V. Science (1997) [Pubmed]
  11. Preclinical assessment of curcumin as a potential therapy for B-CLL. Everett, P.C., Meyers, J.A., Makkinje, A., Rabbi, M., Lerner, A. Am. J. Hematol. (2007) [Pubmed]
  12. Interferon induces NF-kappa B-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-kappa B activation to promote cell survival. Yang, C.H., Murti, A., Pfeffer, L.M. J. Biol. Chem. (2005) [Pubmed]
  13. Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus. Birbach, A., Gold, P., Binder, B.R., Hofer, E., de Martin, R., Schmid, J.A. J. Biol. Chem. (2002) [Pubmed]
  14. Gene expression analysis of primary normal human hepatocytes infected with human hepatitis B virus. Ryu, H.M., Park, S.G., Yea, S.S., Jang, W.H., Yang, Y.I., Jung, G. World J. Gastroenterol. (2006) [Pubmed]
  15. H. pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Maeda, S., Yoshida, H., Ogura, K., Mitsuno, Y., Hirata, Y., Yamaji, Y., Akanuma, M., Shiratori, Y., Omata, M. Gastroenterology (2000) [Pubmed]
  16. Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase. Li, Q., Engelhardt, J.F. J. Biol. Chem. (2006) [Pubmed]
  17. CD40 regulates the processing of NF-kappaB2 p100 to p52. Coope, H.J., Atkinson, P.G., Huhse, B., Belich, M., Janzen, J., Holman, M.J., Klaus, G.G., Johnston, L.H., Ley, S.C. EMBO J. (2002) [Pubmed]
  18. Activation of NF-{kappa}B by the intracellular expression of NF-{kappa}B-inducing kinase acts as a powerful vaccine adjuvant. Andreakos, E., Williams, R.O., Wales, J., Foxwell, B.M., Feldmann, M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Activation of the heterodimeric IkappaB kinase alpha (IKKalpha)-IKKbeta complex is directional: IKKalpha regulates IKKbeta under both basal and stimulated conditions. O'Mahony, A., Lin, X., Geleziunas, R., Greene, W.C. Mol. Cell. Biol. (2000) [Pubmed]
  20. Molecular mechanisms of the effect of herpesvirus saimiri protein StpC on the signaling pathway leading to NF-kappaB activation. Sorokina, E.M., Merlo, J.J., Tsygankov, A.Y. J. Biol. Chem. (2004) [Pubmed]
  21. NESK, a member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and is expressed during the late stages of embryogenesis. Nakano, K., Yamauchi, J., Nakagawa, K., Itoh, H., Kitamura, N. J. Biol. Chem. (2000) [Pubmed]
  22. NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Ling, L., Cao, Z., Goeddel, D.V. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  23. The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). Muzio, M., Natoli, G., Saccani, S., Levrero, M., Mantovani, A. J. Exp. Med. (1998) [Pubmed]
  24. The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors. Baumgartner, M., Sillman, A.L., Blackwood, E.M., Srivastava, J., Madson, N., Schilling, J.W., Wright, J.H., Barber, D.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  25. The NF-kappa B activation in lymphotoxin beta receptor signaling depends on the phosphorylation of p65 at serine 536. Jiang, X., Takahashi, N., Matsui, N., Tetsuka, T., Okamoto, T. J. Biol. Chem. (2003) [Pubmed]
  26. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Song, H.Y., Régnier, C.H., Kirschning, C.J., Goeddel, D.V., Rothe, M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  27. Hydrogen peroxide activates NFkappaB and the interleukin-6 promoter through NFkappaB-inducing kinase. Zhang, J., Johnston, G., Stebler, B., Keller, E.T. Antioxid. Redox Signal. (2001) [Pubmed]
  28. Differential effects of lipopolysaccharide and tumor necrosis factor on monocytic IkappaB kinase signalsome activation and IkappaB proteolysis. Fischer, C., Page, S., Weber, M., Eisele, T., Neumeier, D., Brand, K. J. Biol. Chem. (1999) [Pubmed]
  29. NIK is a component of the EGF/heregulin receptor signaling complexes. Chen, D., Xu, L.G., Chen, L., Li, L., Zhai, Z., Shu, H.B. Oncogene (2003) [Pubmed]
  30. Differential IkappaB kinase activation and IkappaBalpha degradation by interleukin-1beta and tumor necrosis factor-alpha in human U937 monocytic cells. Evidence for additional regulatory steps in kappaB-dependent transcription. Nasuhara, Y., Adcock, I.M., Catley, M., Barnes, P.J., Newton, R. J. Biol. Chem. (1999) [Pubmed]
  31. TNAP, a novel repressor of NF-kappaB-inducing kinase, suppresses NF-kappaB activation. Hu, W.H., Mo, X.M., Walters, W.M., Brambilla, R., Bethea, J.R. J. Biol. Chem. (2004) [Pubmed]
  32. 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. Habib, A.A., Chatterjee, S., Park, S.K., Ratan, R.R., Lefebvre, S., Vartanian, T. J. Biol. Chem. (2001) [Pubmed]
  33. Endothelial activation by angiotensin II through NFkappaB and p38 pathways: Involvement of NFkappaB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin. Costanzo, A., Moretti, F., Burgio, V.L., Bravi, C., Guido, F., Levrero, M., Puri, P.L. J. Cell. Physiol. (2003) [Pubmed]
  34. Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade. Bian, Z.M., Elner, S.G., Yoshida, A., Elner, V.M. Exp. Eye Res. (2003) [Pubmed]
  35. 5-Fluorouracil suppression of NF-KappaB is mediated by the inhibition of IKappab kinase activity in human salivary gland cancer cells. Azuma, M., Yamashita, T., Aota, K., Tamatani, T., Sato, M. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  36. Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin. Loverre, A., Ditonno, P., Crovace, A., Gesualdo, L., Ranieri, E., Pontrelli, P., Stallone, G., Infante, B., Schena, A., Di Paolo, S., Capobianco, C., Ursi, M., Palazzo, S., Battaglia, M., Selvaggi, F.P., Schena, F.P., Grandaliano, G. J. Am. Soc. Nephrol. (2004) [Pubmed]
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