{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:37:36Z","timestamp":1790671056708,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Wnt signalling pathway is a central communication cascade between cells to orchestrate polarity and fate during development and adult tissue homeostasis in various organisms. This pathway can be regulated by different signalling molecules in several steps. One of the coordinators in this pathway is Nemo-like kinase (NLK), which is an atypical proline-directed serine\/threonine mitogen-activated protein (MAP) kinase. Very recently, NLK was established as an essential regulator in different cellular processes and abnormal NLK expression was highlighted to affect the development and progression of various diseases. In this review, we focused on the recent discoveries by using NLK-deficient mice, which show a phenotype in the development and function of organs such as the lung, heart and skeleton. Furthermore, NLK could conduct the function and differentiation of cells from the immune system, in addition to regulating neurodegenerative diseases, such as Huntington\u2019s disease and spinocerebellar ataxias. Overall, generations of NLK-deficient mice have taught us valuable lessons about the role of this kinase in certain diseases and development.<\/jats:p>","DOI":"10.3390\/ijms21239203","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T20:25:49Z","timestamp":1606940749000},"page":"9203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies"],"prefix":"10.3390","volume":"21","author":[{"given":"Ren\u00e9e","family":"Daams","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Translational Cancer Research, Faculty of Medicine, Lund University, 22381 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8875-6440","authenticated-orcid":false,"given":"Ramin","family":"Massoumi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Translational Cancer Research, Faculty of Medicine, Lund University, 22381 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"dev146589","DOI":"10.1242\/dev.146589","article-title":"Wnt signaling in development and tissue homeostasis","volume":"145","author":"Steinhart","year":"2018","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/0012-1606(76)90108-1","article-title":"Effect of the Wingless (wg1) mutation on wing and haltere development in Drosophila melanogaster","volume":"48","author":"Sharma","year":"1976","journal-title":"Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/287795a0","article-title":"Mutations affecting segment number and polarity in Drosophila","volume":"287","author":"Wieschaus","year":"1980","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0092-8674(82)90409-3","article-title":"Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome","volume":"31","author":"Nusse","year":"1982","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0092-8674(84)90209-5","article-title":"Structure and nucleotide sequence of the putative mammary oncogene int-1; proviral insertions leave the protein-encoding domain intact","volume":"39","author":"Nusse","year":"1984","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/0092-8674(87)90038-9","article-title":"The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless","volume":"50","author":"Rijsewijk","year":"1987","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0092-8674(91)90633-A","article-title":"A new nomenclature for int-1 and related genes: The Wnt gene family","volume":"64","author":"Nusse","year":"1991","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4161\/org.4.2.5851","article-title":"Wnt signal transduction pathways","volume":"4","author":"Komiya","year":"2008","journal-title":"Organogenesis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/onc.2016.304","article-title":"Wnt signaling in cancer","volume":"36","author":"Zhan","year":"2017","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1038\/sj.onc.1202653","article-title":"The human F box protein \u03b2-Trcp associates with the Cul1\/Skp1 complex and regulates the stability of \u03b2-catenin","volume":"18","author":"Latres","year":"1999","journal-title":"Oncogene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.cell.2006.10.018","article-title":"Wnt\/\u03b2-Catenin Signaling in Development and Disease","volume":"127","author":"Clevers","year":"2006","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.devcel.2009.06.016","article-title":"Wnt\/beta-catenin signaling: Components, mechanisms, and diseases","volume":"17","author":"MacDonald","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.bbamcr.2006.11.001","article-title":"Atypical mitogen-activated protein kinases: Structure, regulation and functions","volume":"1773","author":"Coulombe","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/0092-8674(94)90579-7","article-title":"Rotation of photoreceptor clusters in the developing drosophila eye requires the nemo gene","volume":"78","author":"Choi","year":"1994","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1073\/pnas.95.3.963","article-title":"Nlk is a murine protein kinase related to Erk\/MAP kinases and localized in the\u2009nucleus","volume":"95","author":"Brott","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/21674","article-title":"The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF","volume":"399","author":"Ishitani","year":"1999","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1128\/MCB.23.4.1379-1389.2003","article-title":"Regulation of Lymphoid Enhancer Factor 1\/T-Cell Factor by Mitogen-Activated Protein Kinase-Related Nemo-Like Kinase-Dependent Phosphorylation in Wnt\/\u03b2-Catenin Signaling","volume":"23","author":"Ishitani","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13397","DOI":"10.1074\/jbc.M109.083246","article-title":"TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling","volume":"285","author":"Li","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20749","DOI":"10.1074\/jbc.M602089200","article-title":"NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor\/lymphoid enhancer factor (TCF\/LEF)","volume":"281","author":"Yamada","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.cellsig.2012.09.017","article-title":"Nemo-like kinase, a multifaceted cell signaling regulator","volume":"25","author":"Ishitani","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1038\/emboj.2012.46","article-title":"NLK positively regulates Wnt\/\u03b2-catenin signalling by phosphorylating LEF1 in neural progenitor cells","volume":"31","author":"Ota","year":"2012","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1101\/gad.1166904","article-title":"Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction","volume":"18","author":"Ohkawara","year":"2004","journal-title":"Genes Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4524","DOI":"10.1073\/pnas.0500679102","article-title":"STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGF\u03b2-activated kinase 1 for STAT3 Ser-727 phosphorylation","volume":"102","author":"Kojima","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","first-page":"1845","article-title":"NLK interacts with 14-3-3\u03b6 to restore the expression of E-cadherin","volume":"43","author":"Chen","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.bbamcr.2014.03.028","article-title":"Nemo-like kinase (NLK) negatively regulates NF-kappa B activity through disrupting the interaction of TAK1 with IKK\u03b2","volume":"1843","author":"Li","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/ncb2028","article-title":"Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex","volume":"12","author":"Ishitani","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9147","DOI":"10.1007\/s13277-015-4159-7","article-title":"The emerging role of Nemo-like kinase (NLK) in the regulation of cancers","volume":"36","author":"Huang","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0006-291X(03)01343-3","article-title":"Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells","volume":"308","author":"Yasuda","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Shaw-Hallgren, G., Masoumi, K.C., Zarrizi, R., Hellman, U., Karlsson, P., Helou, K., and Massoumi, R. (2014). Association of Nuclear-Localized Nemo-Like Kinase with Heat-Shock Protein 27 Inhibits Apoptosis in Human Breast Cancer Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096506"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1097\/CMR.0000000000000576","article-title":"Decreased expression of nemo-like kinase in melanoma is correlated with increased vascularity and metastasis","volume":"29","author":"Yang","year":"2019","journal-title":"Melanoma Res."},{"key":"ref_31","first-page":"6226","article-title":"Effect of NLK on the proliferation and invasion of laryngeal carcinoma cells by regulating CDCP1","volume":"23","author":"Shen","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4341","DOI":"10.1242\/dev.02603","article-title":"Nemo-like kinase (NLK) acts downstream of Notch\/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo","volume":"133","author":"Croce","year":"2006","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1242\/dev.01171","article-title":"Nemo-like kinase is an essential co-activator of Wnt signaling during early zebrafish development","volume":"131","author":"Thorpe","year":"2004","journal-title":"Development"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1021\/bi2002696","article-title":"Possible Involvement of Nemo-like Kinase 1 in Xenopus Oocyte Maturation as a Kinase Responsible for Pumilio1, Pumilio2, and CPEB Phosphorylation","volume":"50","author":"Ota","year":"2011","journal-title":"Biochemistry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1016\/j.febslet.2012.04.005","article-title":"Nemo-like kinase promotes etoposide-induced apoptosis of male germ cell-derived GC-1 cells in vitro","volume":"586","author":"Cheng","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23987","DOI":"10.1038\/srep23987","article-title":"Nemo-like kinase regulates the expression of vascular endothelial growth factor (VEGF) in alveolar epithelial cells","volume":"6","author":"Ke","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1091\/mbc.e16-07-0547","article-title":"NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling","volume":"28","author":"Masoumi","year":"2017","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Liu, R., Khalil, H., Lin, S.-C.J., Sargent, M.A., York, A.J., and Molkentin, J.D. (2016). Nemo-Like Kinase (NLK) Is a Pathological Signaling Effector in the Mouse Heart. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0164897"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1002\/jcp.24625","article-title":"Nemo-Like Kinase Regulates Postnatal Skeletal Homeostasis","volume":"229","author":"Canalis","year":"2014","journal-title":"J. Cell. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nri2360","article-title":"WNT signalling in the immune system: WNT is spreading its wings","volume":"8","author":"Staal","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.it.2018.08.006","article-title":"Canonical and Non-Canonical Wnt Signaling in Immune Cells","volume":"39","author":"Chae","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/s11481-012-9367-y","article-title":"\u03b2-catenin\/TCF-1 pathway in T cell development and differentiation","volume":"7","author":"Ma","year":"2012","journal-title":"J. Neuroimmune Pharmacol. Off. J. Soc. Neuroimmune Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1016\/S0092-8674(02)00709-2","article-title":"WNT signaling and lymphocyte development","volume":"109","author":"Clevers","year":"2002","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.4049\/jimmunol.1800633","article-title":"The Role of WNT Signaling in Mature T Cells: T Cell Factor Is Coming Home","volume":"201","author":"Coffer","year":"2018","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.4049\/jimmunol.2000109","article-title":"Deletion of Nemo-like Kinase in T Cells Reduces Single-Positive CD8(+) Thymocyte Population","volume":"205","author":"Daams","year":"2020","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3600","DOI":"10.1016\/j.celrep.2019.02.087","article-title":"Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells","volume":"26","author":"Fleskens","year":"2019","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1002\/1521-4141(200112)31:12<3580::AID-IMMU3580>3.0.CO;2-N","article-title":"Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk","volume":"31","author":"Kortenjann","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/s41598-017-00842-0","article-title":"Elevated levels of Wnt signaling disrupt thymus morphogenesis and function","volume":"7","author":"Swann","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1038\/s41467-019-11258-x","article-title":"Phosphorylation of MAVS\/VISA by Nemo-like kinase (NLK) for degradation regulates the antiviral innate immune response","volume":"10","author":"Li","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9328","DOI":"10.1523\/JNEUROSCI.3465-12.2013","article-title":"Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1","volume":"33","author":"Ju","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e08493","DOI":"10.7554\/eLife.08493","article-title":"Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy","volume":"4","author":"Todd","year":"2015","journal-title":"Elife"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1093\/hmg\/ddaa061","article-title":"Nemo-like kinase reduces mutant huntingtin levels and mitigates Huntington\u2019s disease","volume":"29","author":"Jiang","year":"2020","journal-title":"Hum. Mol. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:40:47Z","timestamp":1760179247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/9203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,2]]},"references-count":52,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21239203"],"URL":"https:\/\/doi.org\/10.3390\/ijms21239203","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,2]]}}}