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Gene Review

NLK  -  nemo-like kinase

Homo sapiens

Synonyms: LAK1, Nemo-like kinase, Protein LAK1, Serine/threonine-protein kinase NLK
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Disease relevance of NLK

  • Our previous study showed that NLK overexpression induces apoptosis in DLD-1 human colon cancer cells and that apoptosis induction presumably requires a mechanism other than the suppression of beta-catenin-TCF complex [1].
  • A correlation between cytolysis of lymphocytes against a natural killer-resistant melanoma cell line (LAK-like activity) was found, but the role of LAK cells in vivo remains uncertain [2].
  • We have investigated the susceptibility of human foreskin fibroblast (HFF) monolayers infected at low level with human cytomegalovirus (HCMV) strain AD 169, or a clinical HCMV isolate, to lysis mediated by interleukin-2(IL-2)-activated killer cells (LAK) [3].
  • 4. Endothelium infected with herpes simplex virus for very brief periods (4 hr) becomes even more vulnerable to LAK cell-mediated injury [4].

High impact information on NLK

  • Because NLK was recently shown to interact with STAT3, we explored the role of STAT3 in activating this pathway [5].
  • STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation [5].
  • NLK function was found to be redundant with that of the MAP kinase ERK during mesoderm formation and to require the activity of the activating kinase TAK1 [6].
  • From this screen, we isolated a novel RING finger protein that we term NARF (NLK associated RING finger protein) [7].
  • NLK phosphorylated A-Myb, but did not induce A-Myb degradation [8].

Biological context of NLK

  • Second, a loss of multiple NLK phosphorylation sites by truncation of the C-terminal region of c-Myb increases its stability [9].
  • Furthermore, NLK induced the methylation of histone H3 at lysine-9 at A-Myb-bound promoter regions [8].
  • Luciferase reporter gene assay with pNF-kappaB-Luc revealed that NLK could suppress transcription activity of NF-kappaB in a kinase-dependent manner [1].
  • Our results suggest that NLK may suppress a wide range of gene expression, possibly through CBP [1].
  • The induction of wild-type NLK in DLD-1 cells caused suppression of cell growth whereas the kinase-negative mutant did not [10].

Anatomical context of NLK

  • We demonstrate that overnight exposure of LGL to as little as 1 nM okadaic acid induced an increase in natural killing against the K562 cell line, but does not induce LAK activity [11].
  • Soluble HLA class I molecules in malignant pleural and peritoneal effusions and its possible role on NK and LAK cytotoxicity [12].
  • The study has been performed on monocyte-depleted peripheral blood MNCs by using, the K-562 cell line as a target for NK activity and the HL-60 cell line for as a target LAK activity [13].

Regulatory relationships of NLK

  • Furthermore, the expression of the STAT3(534-770) region in the nuclei of STAT3-knockdown cells enhanced the IL-6-induced NLK activation in a dose-dependent manner but not the TGFbeta-induced NLK activation [5].

Other interactions of NLK

  • However, it appeared that transcription co-activators of NF-kappaB, such as CREB binding protein (CBP)/p300, were likely to be the direct targets of NLK, rather than NF-kappaB itself [1].
  • Depletion of STAT3 diminished the IL-6-induced NLK activation by >80% without inhibiting IL-6-induced TAK1 activation or its nuclear entry [5].
  • Our results suggest that overexpression of NLK may have targets other than TCF for induction of apoptosis in human colon carcinoma cells [10].

Analytical, diagnostic and therapeutic context of NLK


  1. Nemo-like kinase suppresses a wide range of transcription factors, including nuclear factor-kappaB. Yasuda, J., Yokoo, H., Yamada, T., Kitabayashi, I., Sekiya, T., Ichikawa, H. Cancer Sci. (2004) [Pubmed]
  2. Chemotherapy in combination with biomodulation: a 5-year experience with cyclophosphamide and interleukin-2. Mitchell, M.S. Semin. Oncol. (1992) [Pubmed]
  3. Low-dose human cytomegalovirus infection of human fibroblast cultures induces lymphokine-activated killer cell resistance: interferon-beta-mediated target cell protection does not correlate with up-regulation of HLA class I surface molecules. Hamprecht, K., Steinmassl, M. Immunology (1994) [Pubmed]
  4. Excessive vulnerability of herpes-infected endothelium to lymphokine-activated lymphocytes: a possible role in lethal viral pneumonitis following bone marrow transplantation. Vercellotti, G.M., Kotasek, D., Jacob, H.S. Trans. Assoc. Am. Physicians (1988) [Pubmed]
  5. STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Kojima, H., Sasaki, T., Ishitani, T., Iemura, S., Zhao, H., Kaneko, S., Kunimoto, H., Natsume, T., Matsumoto, K., Nakajima, K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo. R??ttinger, E., Croce, J., Lhomond, G., Besnardeau, L., Gache, C., Lepage, T. Development (2006) [Pubmed]
  7. NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). Yamada, M., Ohnishi, J., Ohkawara, B., Iemura, S., Satoh, K., Hyodo-Miura, J., Kawachi, K., Natsume, T., Shibuya, H. J. Biol. Chem. (2006) [Pubmed]
  8. The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the association with coactivator CBP and methylating histone H3. Kurahashi, T., Nomura, T., Kanei-Ishii, C., Shinkai, Y., Ishii, S. Mol. Biol. Cell (2005) [Pubmed]
  9. Differential sensitivity of v-Myb and c-Myb to Wnt-1-induced protein degradation. Kanei-Ishii, C., Nomura, T., Tanikawa, J., Ichikawa-Iwata, E., Ishii, S. J. Biol. Chem. (2004) [Pubmed]
  10. Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells. Yasuda, J., Tsuchiya, A., Yamada, T., Sakamoto, M., Sekiya, T., Hirohashi, S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  11. Activation of peripheral large granular lymphocytes with the serine/threonine phosphatase inhibitor, okadaic acid. McVicar, D.W., Mason, A.T., Bere, E.W., Ortaldo, J.R. Eur. J. Immunol. (1994) [Pubmed]
  12. Soluble HLA class I molecules in malignant pleural and peritoneal effusions and its possible role on NK and LAK cytotoxicity. Amirghofran, Z., Sheikhi, A.K., Kumar, P.V., Saberi Firouzi, M. J. Cancer Res. Clin. Oncol. (2002) [Pubmed]
  13. Natural killer and lymphokine-activated killer activity in HLA-B8,DR3-positive subjects. Caruso, C., Candore, G., Colucci, A.T., Cigna, D., Modica, M.A., Tantillo, G., Salerno, A. Hum. Immunol. (1993) [Pubmed]
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