Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Tohru IshitaniEmail author
  • Shizuka Ishitani
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101750


Historical Background

The protein kinase NLK was originally identified as nemo, a gene involved in Drosophila melanogaster eye development. D. melanogaster compound eyes are made up of hexagonal units called ommatidia. A mutation in nemo affects the movement of ommatidia cells, causing them to acquire a squared shape (Choi and Benzer 1994) which is reflected in the name “nemo,” Korean for square. In 1998, Brott et al. isolated the mouse homolog of nemo and named it “Nemo-like kinase (NLK).” Meneghini et al. (1999) and Rocheleau et al. (1999) found that the Caenorhabditis elegans loss-of-intestine-1 (lit-1) mutant, which lacks the endoderm, has a mutation in a homolog of NLK. This homolog phosphorylates Posterior pharynx defect protein 1 (POP-1) to relieve POP-1-mediated inhibition of gene expression required for endoderm formation. POP-1 is a homolog of the mammalian T-cell factor/lymphoid enhancer factor (Tcf/Lef), a key component of the Wnt/β-catenin...

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  1. Braid LR, Lee W, Uetrecht AC, Swarup S, Papaianni G, Heiler A, Verheyen EM. Nemo phosphorylates even-skipped and promotes eve-mediated repression of odd-skipped in even parasegments during Drosophila embryogenesis. Dev Biol. 2010;343:178–89. doi:10.1016/j.ydbio.2010.04.008.CrossRefPubMedGoogle Scholar
  2. Brott BK, Pinsky BA, Erikson RL. Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus. Proc Natl Acad Sci U S A. 1998;95:963–8.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Chiu JC, Ko HW, Edery I. NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed. Cell. 2011;145:357–70. doi:10.1016/j.cell.2011.04.002.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Choi KW, Benzer S. Rotation of photoreceptor clusters in the developing Drosophila eye requires the nemo gene. Cell. 1994;78:125–36.CrossRefPubMedGoogle Scholar
  5. Cichocki F, Felices M, McCullar V, Presnell SR, Al-Attar A, Lutz CT, Miller JS. Cutting edge: microRNA-181 promotes human NK cell development by regulating Notch signaling. J Immunol. 2011;187:6171–5. doi:10.4049/jimmunol.1100835.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cui G, Li Z, Shao B, Zhao L, Zhou Y, Lu T, Wang J, Shi X, Wang J, Zuo G, Zhu W, Shen A. Clinical and biological significance of nemo-like kinase expression in glioma. J Clin Neurosci. 2011;18:271–5. doi:10.1016/j.jocn.2010.05.037.CrossRefPubMedGoogle Scholar
  7. Emami KH, Brown LG, Pitts TE, Sun X, Vessella RL, Corey E. Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. Prostate. 2009;69:1481–92. doi:10.1002/pros.20998.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Huang Y, Yang Y, He Y, Huang C, Meng X, Li J. MicroRNA-208a potentiates angiotensin II-triggered cardiac myoblasts apoptosis via inhibiting Nemo-like kinase (NLK). Curr Pharm Des. 2016;22:4868–75.CrossRefPubMedGoogle Scholar
  9. Ishitani T, Ishitani S. Nemo-like kinase, a multifaceted cell signaling regulator. Cell Signal. 2013;25:190–7. doi:10.1016/j.cellsig.2012.09.017.CrossRefPubMedGoogle Scholar
  10. Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N, Waterman M, Bowerman B, Clevers H, Shibuya H, Matsumoto K. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature. 1999;399:798–802. doi:10.1038/21674.CrossRefPubMedGoogle Scholar
  11. Ishitani T, Ninomiya-Tsuji J, Matsumoto K. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol Cell Biol. 2003a;23:1379–89.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K. The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Mol Cell Biol. 2003b;23:131–9.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Ishitani T, Ishitani S, Matsumoto K, Itoh M. Nemo-like kinase is involved in NGF-induced neurite outgrowth via phosphorylating MAP1B and paxillin. J Neurochem. 2009;111:1104–18. doi:10.1111/j.1471-4159.2009.06400.x.CrossRefPubMedGoogle Scholar
  14. Ishitani T, Hirao T, Suzuki M, Isoda M, Ishitani S, Harigaya K, Kitagawa M, Matsumoto K, Itoh M. Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. Nat Cell Biol. 2010;12:278–85. doi:10.1038/ncb2028.CrossRefPubMedGoogle Scholar
  15. Ishitani S, Inaba K, Matsumoto K, Ishitani T. Homodimerization of Nemo-like kinase is essential for activation and nuclear localization. Mol Biol Cell. 2011;22:266–77. doi:10.1091/mbc.E10-07-0605.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, Deng C, Wauthier E, Reid LM, Ye QH, Qin LX, Yang W, Wang HY, Tang ZY, Croce CM, Wang XW. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology. 2009;50:472–80. doi:10.1002/hep.22989.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ju H, Kokubu H, Todd TW, Kahle JJ, Kim S, Richman R, Chirala K, Orr HT, Zoghbi HY, Lim J. Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1. J Neurosci. 2013;33:9328–36. doi:10.1523/JNEUROSCI.3465-12.2013.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jung KH, Kim JK, Noh JH, Eun JW, Bae HJ, Xie HJ, Ahn YM, Park WS, Lee JY, Nam SW. Targeted disruption of Nemo-like kinase inhibits tumor cell growth by simultaneous suppression of cyclin D1 and CDK2 in human hepatocellular carcinoma. J Cell Biochem. 2010;110:687–96. doi:10.1002/jcb.22579.CrossRefPubMedGoogle Scholar
  19. Kanei-Ishii C, Ninomiya-Tsuji J, Tanikawa J, Nomura T, Ishitani T, Kishida S, Kokura K, Kurahashi T, Ichikawa-Iwata E, Kim Y, Matsumoto K, Ishii S. Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. Genes Dev. 2004;18:816–29. doi:10.1101/gad.1170604.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ke H, Masoumi KC, Ahlqvist K, Seckl MJ, Rydell-Törmänen K, Massoumi R. Nemo-like kinase regulates the expression of vascular endothelial growth factor (VEGF) in alveolar epithelial cells. Sci Rep. 2016;6. doi:10.1038/srep23987.Google Scholar
  21. Kim S, Kim Y, Lee J, Chung J. Regulation of FOXO1 by TAK1-Nemo-like kinase pathway. J Biol Chem. 2010;285:8122–9. doi:10.1074/jbc.M110.101824.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kim WT, Kim H, Katanaev VL, Joon Lee S, Ishitani T, Cha B, Han JK, Jho EH. Dual functions of DP1 promote biphasic Wnt-on and Wnt-off states during anteroposterior neural patterning. EMBO J. 2012;31:3384–97. doi:10.1038/emboj.2012.181.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kojima H, Sasaki T, Ishitani T, Iemura S, Zhao H, Kaneko S, Kunimoto H, Natsume T, Matsumoto K, Nakajima K. STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc Natl Acad Sci U S A. 2005;102:4524–9. doi:10.1073/pnas.0500679102.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kortenjann M, Nehls M, Smith AJ, Carsetti R, Schüler J, Köhler G, Boehm T. Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk. Eur J Immunol. 2001;31:3580–7. doi:10.1002/1521-4141(200112)31:12<3580::AID-IMMU3580>3.0.CO;2-N.CrossRefPubMedGoogle Scholar
  25. Kurahashi T, Nomura T, Kanei-Ishii C, Shinkai Y, Ishii S. The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the association with coactivator CBP and methylating histone H3. Mol Biol Cell. 2005;16:4705–13. doi:10.1091/mbc.E05-05-0470.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Mendes-Pereira AM, Lord CJ, Ashworth A. NLK is a novel therapeutic target for PTEN deficient tumour cells. PLoS One. 2012;7:e47249. doi:10.1371/journal.pone.0047249.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Meneghini MD, Ishitani T, Carter JC, Hisamoto N, Ninomiya-Tsuji J, Thorpe CJ, Hamill DR, Matsumoto K, Bowerman B. MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans. Nature. 1999;399:793–7. doi:10.1038/21666.CrossRefPubMedGoogle Scholar
  28. Mirkovic I, Gault WJ, Rahnama M, Jenny A, Gaengel K, Bessette D, Gottardi CJ, Verheyen EM, Mlodzik M. Nemo kinase phosphorylates β-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-β-catenin. Nat Struct Mol Biol. 2011;18:665–72. doi:10.1038/nsmb.2049.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Morillo SA, Braid LR, Verheyen EM, Rebay I. Nemo phosphorylates Eyes absent and enhances output from the Eya-Sine oculis transcriptional complex during Drosophila retinal determination. Dev Biol. 2012;365:267–76. doi:10.1016/j.ydbio.2012.02.030.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Ohkawara B, Shirakabe K, Hyodo-Miura J, Matsuo R, Ueno N, Matsumoto K, Shibuya H. Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction. Genes Dev. 2004;18:381–6. doi:10.1101/gad.1166904.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Ohnishi E, Goto T, Sato A, Kim MS, Iemura S, Ishitani T, Natsume T, Ohnishi J, Shibuya H. Nemo-like kinase, an essential effector of anterior formation, functions downstream of p38 mitogen-activated protein kinase. Mol Cell Biol. 2010;30:675–83. doi:10.1128/MCB.00576-09.CrossRefPubMedGoogle Scholar
  32. Ota R, Kotani T, Yamashita M. Possible involvement of Nemo-like kinase 1 in Xenopus oocyte maturation as a kinase responsible for Pumilio1, Pumilio2, and CPEB phosphorylation. Biochemistry. 2011;50:5648–59. doi:10.1021/bi2002696.CrossRefPubMedGoogle Scholar
  33. Ota S, Ishitani S, Shimizu N, Matsumoto K, Itoh M, Ishitani T. NLK positively regulates Wnt/β-catenin signalling by phosphorylating LEF1 in neural progenitor cells. EMBO J. 2012;31:1904–15. doi:10.1038/emboj.2012.46.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Rocheleau CE, Yasuda J, Shin TH, Lin R, Sawa H, Okano H, Priess JR, Davis RJ, Mello CC. WRM-1 activates the LIT-1 protein kinase to transduce anterior/posterior polarity signals in C. elegans. Cell. 1999;97:717–26.CrossRefPubMedGoogle Scholar
  35. Sa JK, Yoon Y, Kim M, Kim Y, Cho HJ, Lee JK, Kim GS, Han S, Kim WJ, Shin YJ, Joo KM, Paddison PJ, Ishitani T, Lee J, Nam DH. In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma. Oncotarget. 2015;6:20145–59. doi:10.18632/oncotarget.3980.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Satoh K, Ohnishi J, Sato A, Takeyama M, Iemura S, Natsume T, Shibuya H. Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development. Mol Cell Biol. 2007;27:7623–30. doi:10.1128/MCB.01481-07.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Shen Q, Bae HJ, Eun JW, Kim HS, Park SJ, Shin WC, Lee EK, Park S, Park WS, Lee JY, Nam SW. MiR-101 functions as a tumor suppressor by directly targeting nemo-like kinase in liver cancer. Cancer Lett. 2014;344:204–11. doi:10.1016/j.canlet.2013.10.030.CrossRefPubMedGoogle Scholar
  38. Thorpe CJ, Moon RT. Nemo-like kinase is an essential co-activator of Wnt signaling during early zebrafish development. Development. 2004;131:2899–909. doi:10.1242/dev.01171.CrossRefPubMedGoogle Scholar
  39. Todd TW, Kokubu H, Miranda HC, Cortes CJ, La Spada AR, Lim J. Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy. Elizab Theatr. 2015;4:e08493. doi:10.7554/eLife.08493.CrossRefGoogle Scholar
  40. Wang J, Yang ZH, Chen H, Li HH, Chen LY, Zhu Z, Zou Y, Ding CC, Yang J, He ZW. Nemo-like kinase as a negative regulator of nuclear receptor Nurr1 gene transcription in prostate cancer. BMC Cancer. 2016;16:257. doi:10.1186/s12885-016-2291-4.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Yamada M, Ohnishi J, Ohkawara B, Iemura S, Satoh K, Hyodo-Miura J, Kawachi K, Natsume T, Shibuya H. NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). J Biol Chem. 2006;281:20749–60. doi:10.1074/jbc.M602089200.CrossRefPubMedGoogle Scholar
  42. Yuan HX, Wang Z, FX Y, Li F, Russell RC, Jewell JL, Guan KL. NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition. Genes Dev. 2015;29:2362–76. doi:10.1101/gad.265116.115.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Zeng YA, Rahnama M, Wang S, Sosu-Sedzorme W, Verheyen EM. Drosophila Nemo antagonizes BMP signaling by phosphorylation of Mad and inhibition of its nuclear accumulation. Development. 2007;134:2061–71. doi:10.1242/dev.02853.CrossRefPubMedGoogle Scholar
  44. Zhang HH, Li SZ, Zhang ZY, XM H, Hou PN, Gao L, Du RL, Zhang XD. Nemo-like kinase is critical for p53 stabilization and function in response to DNA damage. Cell Death Differ. 2014;21:1656–63. doi:10.1038/cdd.2014.78.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zhang ZY, Li SZ, Zhang HH, Wu QR, Gong J, Liang T, Gao L, Xing NN, Liu WB, Du RL, Zhang XD. Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1β-stimulated C/EBP signaling pathway. Mol Cell Biol. 2015;35:778–88. doi:10.1128/MCB.01228-14.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Zhou X, Ren Y, Zhang J, Zhang C, Zhang K, Han L, Kong L, Wei J, Chen L, Yang J, Wang Q, Zhang J, Yang Y, Jiang T, Li M, Kang C. HOTAIR is a therapeutic target in glioblastoma. Oncotarget. 2015;6:8353–65. doi:10.18632/oncotarget.3229.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Cell Regulation Systems, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
  2. 2.Institute for Molecular and Cellular RegulationGunma UniversityMaebashiJapan