Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5HODDD)

• DOT Name: Mitogen-activated protein kinase kinase kinase 12 (MAP3K12)
• Synonyms: EC 2.7.11.25; Dual leucine zipper bearing kinase; DLK; Leucine-zipper protein kinase; ZPK; MAPK-upstream kinase; MUK; Mixed lineage kinase
• Gene Name: MAP3K12
• Related Disease:
  B-cell neoplasm
  Breast carcinoma
  Acute lymphocytic leukaemia
  Alzheimer disease
  Cardiac failure
  Childhood acute lymphoblastic leukemia
  Congestive heart failure
  Myelodysplastic syndrome
  Breast cancer
  Lung cancer
  Lung carcinoma
  Melanoma
  Neoplasm
  Neuroblastic tumor
  Neuroblastoma
  Parkinson disease
  Subarachnoid hemorrhage
• UniProt ID: M3K12_HUMAN
• PDB ID: 5CEN; 5CEO; 5CEP; 5CEQ; 5VO1; 5VO2; 8DEG; 8OUR; 8OUS; 8OUT
• EC Number: 2.7.11.25
• Pfam ID: PF07714
• Sequence:
  MACLHETRTPSPSFGGFVSTLSEASMRKLDPDTSDCTPEKDLTPTHVLQLHEQDAGGPGG
  AAGSPESRASRVRADEVRLQCQSGSGFLEGLFGCLRPVWTMIGKAYSTEHKQQQEDLWEV
  PFEEILDLQWVGSGAQGAVFLGRFHGEEVAVKKVRDLKETDIKHLRKLKHPNIITFKGVC
  TQAPCYCILMEFCAQGQLYEVLRAGRPVTPSLLVDWSMGIAGGMNYLHLHKIIHRDLKSP
  NMLITYDDVVKISDFGTSKELSDKSTKMSFAGTVAWMAPEVIRNEPVSEKVDIWSFGVVL
  WELLTGEIPYKDVDSSAIIWGVGSNSLHLPVPSSCPDGFKILLRQCWNSKPRNRPSFRQI
  LLHLDIASADVLSTPQETYFKSQAEWREEVKLHFEKIKSEGTCLHRLEEELVMRRREELR
  HALDIREHYERKLERANNLYMELNALMLQLELKERELLRREQALERRCPGLLKPHPSRGL
  LHGNTMEKLIKKRNVPQKLSPHSKRPDILKTESLLPKLDAALSGVGLPGCPKGPPSPGRS
  RRGKTRHRKASAKGSCGDLPGLRTAVPPHEPGGPGSPGGLGGGPSAWEACPPALRGLHHD
  LLLRKMSSSSPDLLSAALGSRGRGATGGAGDPGSPPPARGDTPPSEGSAPGSTSPDSPGG
  AKGEPPPPVGPGEGVGLLGTGREGTSGRGGSRAGSQHLTPAALLYRAAVTRSQKRGISSE
  EEEGEVDSEVELTSSQRWPQSLNMRQSLSTFSSENPSDGEEGTASEPSPSGTPEVGSTNT
  DERPDERSDDMCSQGSEIPLDPPPSEVIPGPEPSSLPIPHQELLRERGPPNSEDSDCDST
  ELDNSNSVDALRPPASLPP
• Function: Part of a non-canonical MAPK signaling pathway. Activated by APOE, enhances the AP-1-mediated transcription of APP, via a MAP kinase signal transduction pathway composed of MAP2K7 and MAPK1/ERK2 and MAPK3/ERK1. May be an activator of the JNK/SAPK pathway.
• Tissue Specificity: Highly expressed in brain and kidney.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[2]
Lung cancer	DISCM4YA	Limited	Altered Expression	[7]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[7]
Melanoma	DIS1RRCY	Limited	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]
Neuroblastic tumor	DISKWPS1	Limited	Altered Expression	[8]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[8]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[9]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mitogen-activated protein kinase kinase kinase 12 (MAP3K12).	[20]

References

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• [2] Pro-necrotic molecules impact local immunosurveillance in human breast cancer.Oncoimmunology. 2017 Apr 17;6(4):e1299302. doi: 10.1080/2162402X.2017.1299302. eCollection 2017.
• [3] Gene expression pattern contributing to prognostic factors in childhood acute lymphoblastic leukemia.Leuk Lymphoma. 2013 Feb;54(2):310-4. doi: 10.3109/10428194.2012.710330. Epub 2012 Sep 8.
• [4] Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease.J Med Chem. 2017 Oct 12;60(19):8083-8102. doi: 10.1021/acs.jmedchem.7b00843. Epub 2017 Sep 20.
• [5] Tissue distribution and functional expression of a cDNA encoding a novel mixed lineage kinase.J Mol Cell Cardiol. 2001 Sep;33(9):1739-50. doi: 10.1006/jmcc.2001.1437.
• [6] Identification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction.Blood. 2001 Jul 15;98(2):422-7. doi: 10.1182/blood.v98.2.422.
• [7] Relationship between DLK1 gene promoter region DNA methylation and non-small cell lung cancer biological behavior.Oncol Lett. 2017 Jun;13(6):4123-4126. doi: 10.3892/ol.2017.6019. Epub 2017 Apr 10.
• [8] Differential expression of delta-like gene and protein in neuroblastoma, ganglioneuroblastoma and ganglioneuroma.Mod Pathol. 2005 May;18(5):656-62. doi: 10.1038/modpathol.3800335.
• [9] A longitudinal program for biomarker development in Parkinson's disease: a feasibility study.Mov Disord. 2009 Oct 30;24(14):2081-90. doi: 10.1002/mds.22690.
• [10] DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats.Neurobiol Dis. 2017 Jul;103:133-143. doi: 10.1016/j.nbd.2017.04.006. Epub 2017 Apr 8.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.
• [13] 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.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] 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.
• [22] Bisphenol A enhances adipogenic differentiation of human adipose stromal/stem cells. J Mol Endocrinol. 2014 Dec;53(3):345-53. doi: 10.1530/JME-14-0052. Epub 2014 Aug 20.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.