Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2LETFS)

• DOT Name: Serine/threonine-protein kinase NLK (NLK)
• Synonyms: EC 2.7.11.24; Nemo-like kinase; Protein LAK1
• Gene Name: NLK
• Related Disease:
  Spinocerebellar ataxia type 1
  Adenoma
  Advanced cancer
  Burkitt lymphoma
  Cardiac arrest
  Cardiac failure
  Colonic neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Congestive heart failure
  Glioma
  Hepatocellular carcinoma
  Lentivirus infection
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Melanoma
  Metastatic malignant neoplasm
  Mood disorder
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Pulmonary disease
  Subarachnoid hemorrhage
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Colon cancer
  Colon carcinoma
  Familial adenomatous polyposis
  Liver cancer
  Nasopharyngeal carcinoma
  Niemann-Pick disease type C
  Small-cell lung cancer
  Squamous cell carcinoma
  Adult glioblastoma
  Epithelial ovarian cancer
  Gallbladder cancer
  Gallbladder carcinoma
  Glioblastoma multiforme
  Neuroblastoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: NLK_HUMAN
• EC Number: 2.7.11.24
• Pfam ID: PF00069
• Sequence:
  MSLCGARANAKMMAAYNGGTSAAAAGHHHHHHHHLPHLPPPHLHHHHHPQHHLHPGSAAA
  VHPVQQHTSSAAAAAAAAAAAAAMLNPGQQQPYFPSPAPGQAPGPAAAAPAQVQAAAAAT
  VKAHHHQHSHHPQQQLDIEPDRPIGYGAFGVVWSVTDPRDGKRVALKKMPNVFQNLVSCK
  RVFRELKMLCFFKHDNVLSALDILQPPHIDYFEEIYVVTELMQSDLHKIIVSPQPLSSDH
  VKVFLYQILRGLKYLHSAGILHRDIKPGNLLVNSNCVLKICDFGLARVEELDESRHMTQE
  VVTQYYRAPEILMGSRHYSNAIDIWSVGCIFAELLGRRILFQAQSPIQQLDLITDLLGTP
  SLEAMRTACEGAKAHILRGPHKQPSLPVLYTLSSQATHEAVHLLCRMLVFDPSKRISAKD
  ALAHPYLDEGRLRYHTCMCKCCFSTSTGRVYTSDFEPVTNPKFDDTFEKNLSSVRQVKEI
  IHQFILEQQKGNRVPLCINPQSAAFKSFISSTVAQPSEMPPSPLVWE
• Function: Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination. Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Negative regulator of the canonical Wnt/beta-catenin signaling pathway. Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1. Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes. Negative regulator of the Notch signaling pathway. Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1. Negative regulator of the MYB family of transcription factors. Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP. Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself. Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1. Upon IL1B stimulus, cooperates with ATF5 to activate the transactivation activity of C/EBP subfamily members. Phosphorylates ATF5 but also stabilizes ATF5 protein levels in a kinase-independent manner. Acts as an inhibitor of the mTORC1 complex in response to osmotic stress by mediating phosphorylation of RPTOR, thereby preventing recruitment of the mTORC1 complex to lysosomes.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  FoxO sig.ling pathway (hsa04068)
  Wnt sig.ling pathway (hsa04310)
  Adherens junction (hsa04520)
• Reactome Pathway: Ca2+ pathway (R-HSA-4086398)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia type 1	DISF7BO2	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[4]
Cardiac arrest	DIS9DIA4	Strong	Altered Expression	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Lentivirus infection	DISX17PY	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[12]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[13]
Melanoma	DIS1RRCY	Strong	Altered Expression	[14]
Metastatic malignant neoplasm	DIS86UK6	Strong	Posttranslational Modification	[15]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[16]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[16]
Pulmonary disease	DIS6060I	Strong	Altered Expression	[17]
Subarachnoid hemorrhage	DISI7I8Y	Strong	ModifyingMutation	[18]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[19]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[19]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[20]
Colon cancer	DISVC52G	moderate	Biomarker	[20]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[20]
Familial adenomatous polyposis	DISW53RE	moderate	Biomarker	[21]
Liver cancer	DISDE4BI	moderate	Biomarker	[20]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[21]
Niemann-Pick disease type C	DIS492ZO	moderate	Altered Expression	[21]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[22]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[23]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[24]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[25]
Gallbladder cancer	DISXJUAF	Limited	Biomarker	[26]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[26]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[24]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[27]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[28]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[25]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[25]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase NLK (NLK).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase NLK (NLK).	[30]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein kinase NLK (NLK).	[31]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine/threonine-protein kinase NLK (NLK).	[33]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein kinase NLK (NLK).	[34]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Serine/threonine-protein kinase NLK (NLK).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/threonine-protein kinase NLK (NLK).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine/threonine-protein kinase NLK (NLK).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein kinase NLK (NLK).	[40]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein kinase NLK (NLK).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein kinase NLK (NLK).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Serine/threonine-protein kinase NLK (NLK).	[38]

References

• [1] Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1.J Neurosci. 2013 May 29;33(22):9328-36. doi: 10.1523/JNEUROSCI.3465-12.2013.
• [2] Upregulation of nemo-like kinase is an independent prognostic factor in colorectal cancer.World J Gastroenterol. 2015 Aug 7;21(29):8836-47. doi: 10.3748/wjg.v21.i29.8836.
• [3] Expression of Nemo-like kinase in cervical squamous cell carcinoma: a clinicopathological study.Onco Targets Ther. 2018 Feb 8;11:743-749. doi: 10.2147/OTT.S154188. eCollection 2018.
• [4] Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma.BMC Cancer. 2017 Nov 13;17(1):761. doi: 10.1186/s12885-017-3711-9.
• [5] Nemo-Like Kinase (NLK) Is a Pathological Signaling Effector in the Mouse Heart.PLoS One. 2016 Oct 20;11(10):e0164897. doi: 10.1371/journal.pone.0164897. eCollection 2016.
• [6] Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells.Biochem Biophys Res Commun. 2003 Aug 22;308(2):227-33. doi: 10.1016/s0006-291x(03)01343-3.
• [7] Nemolike kinase expression predicts poor survival in colorectal cancer.Mol Med Rep. 2015 Feb;11(2):1181-7. doi: 10.3892/mmr.2014.2851. Epub 2014 Nov 3.
• [8] Nemo-like kinase (NLK) primes colorectal cancer progression by releasing the E2F1 complex from HDAC1.Cancer Lett. 2018 Sep 1;431:43-53. doi: 10.1016/j.canlet.2018.05.032. Epub 2018 May 25.
• [9] CACNA2D3 is downregulated in gliomas and functions as a tumor suppressor.Mol Carcinog. 2017 Mar;56(3):945-959. doi: 10.1002/mc.22548. Epub 2016 Sep 22.
• [10] Prognostic significance of Nemo-like kinase expression in patients with hepatocellular carcinoma.Tumour Biol. 2015 Nov;36(11):8447-53. doi: 10.1007/s13277-015-3609-6. Epub 2015 May 29.
• [11] Lentivirusdelivered nemolike kinase small interfering RNA inhibits laryngeal cancer cell proliferation in vitro.Mol Med Rep. 2015 Oct;12(4):5619-24. doi: 10.3892/mmr.2015.4189. Epub 2015 Aug 6.
• [12] Overexpression of Nemo-like Kinase Promotes the Proliferation and Invasion of Lung Cancer Cells and Indicates Poor Prognosis.Curr Cancer Drug Targets. 2019;19(8):674-680. doi: 10.2174/1568009618666181119150521.
• [13] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [14] Decreased expression of nemo-like kinase in melanoma is correlated with increased vascularity and metastasis.Melanoma Res. 2019 Aug;29(4):376-381. doi: 10.1097/CMR.0000000000000576.
• [15] Targeted design and identification of AC1NOD4Q to block activity of HOTAIR by abrogating the scaffold interaction with EZH2.Clin Epigenetics. 2019 Feb 14;11(1):29. doi: 10.1186/s13148-019-0624-2.
• [16] Nemo-like kinase as a negative regulator of nuclear receptor Nurr1 gene transcription in prostate cancer.BMC Cancer. 2016 Mar 31;16:257. doi: 10.1186/s12885-016-2291-4.
• [17] NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin.J Hematol Oncol. 2015 Oct 26;8:120. doi: 10.1186/s13045-015-0203-8.
• [18] Expression of Nemo-like kinase (NLK) in the brain in a rat experimental subarachnoid hemorrhage model.Cell Biochem Biophys. 2013 Jul;66(3):671-80. doi: 10.1007/s12013-012-9511-6.
• [19] Nemo-like kinase associated with proliferation and apoptosis by c-Myb degradation in breast cancer.PLoS One. 2013 Jul 23;8(7):e69148. doi: 10.1371/journal.pone.0069148. Print 2013.
• [20] 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 Jun 1;110(3):687-96. doi: 10.1002/jcb.22579.
• [21] The effect of EBV on WIF1, NLK, and APC gene methylation and expression in gastric carcinoma and nasopharyngeal cancer.J Med Virol. 2017 Oct;89(10):1844-1851. doi: 10.1002/jmv.24863. Epub 2017 Jul 6.
• [22] Lentivirus-mediated knockdown of NLK inhibits small-cell lung cancer growth and metastasis.Drug Des Devel Ther. 2016 Nov 15;10:3737-3746. doi: 10.2147/DDDT.S87435. eCollection 2016.
• [23] MicroRNA-92b promotes tumor growth and activation of NF-B signaling via regulation of NLK in oral squamous cell carcinoma.Oncol Rep. 2015 Dec;34(6):2961-8. doi: 10.3892/or.2015.4323.
• [24] In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma.Oncotarget. 2015 Aug 21;6(24):20145-59. doi: 10.18632/oncotarget.3980.
• [25] Common variation in Nemo-like kinase is associated with risk of ovarian cancer.Cancer Epidemiol Biomarkers Prev. 2012 Mar;21(3):523-8. doi: 10.1158/1055-9965.EPI-11-0797. Epub 2012 Jan 17.
• [26] NLK is a key regulator of proliferation and migration in gallbladder carcinoma cells.Mol Cell Biochem. 2012 Oct;369(1-2):27-33. doi: 10.1007/s11010-012-1365-0. Epub 2012 Jun 24.
• [27] microRNA-221 Enhances MYCN via Targeting Nemo-like Kinase and Functions as an Oncogene Related to Poor Prognosis in Neuroblastoma.Clin Cancer Res. 2017 Jun 1;23(11):2905-2918. doi: 10.1158/1078-0432.CCR-16-1591. Epub 2016 Dec 21.
• [28] Knockdown of Nemolike kinase promotes metastasis in nonsmallcell lung cancer.Oncol Rep. 2019 Sep;42(3):1090-1100. doi: 10.3892/or.2019.7226. Epub 2019 Jul 9.
• [29] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [30] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [31] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [32] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [33] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [34] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [35] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [36] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [37] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [38] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [39] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [40] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.