Skip to main content
SpringerLink
Log in

NLK

  • Reference work entry
  • First Online:
Encyclopedia of Signaling Molecules

  • 232 Accesses

Synonyms

Nemo-like kinase

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...

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 4,499.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 4,499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Choi KW, Benzer S. Rotation of photoreceptor clusters in the developing Drosophila eye requires the nemo gene. Cell. 1994;78:125–36.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Tohru Ishitani

  2. Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan

    Shizuka Ishitani

Authors
  1. Tohru Ishitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shizuka Ishitani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tohru Ishitani .

Editor information

Editors and Affiliations

  1. Department of Molecular Science and Technology, Ajou University, Suwon, Korea

    Sangdun Choi

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Ishitani, T., Ishitani, S. (2018). NLK. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101750

Download citation

Publish with us

Policies and ethics

Search

Navigation