Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKB0RA8)

DOT Name Misshapen-like kinase 1 (MINK1)
Synonyms EC 2.7.11.1; GCK family kinase MiNK; MAPK/ERK kinase kinase kinase 6; MEK kinase kinase 6; MEKKK 6; Misshapen/NIK-related kinase; Mitogen-activated protein kinase kinase kinase kinase 6
Gene Name MINK1
Related Disease
Advanced cancer ( )
Atrial fibrillation ( )
Cardiac disease ( )
Fibrosarcoma ( )
Progressive supranuclear palsy ( )
Neoplasm ( )
Autoimmune disease ( )
Long QT syndrome ( )
Nervous system inflammation ( )
Osteoarthritis ( )
UniProt ID
MINK1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
2.7.11.1
Pfam ID
PF00780 ; PF00069
Sequence
MGDPAPARSLDDIDLSALRDPAGIFELVEVVGNGTYGQVYKGRHVKTGQLAAIKVMDVTE
DEEEEIKQEINMLKKYSHHRNIATYYGAFIKKSPPGNDDQLWLVMEFCGAGSVTDLVKNT
KGNALKEDCIAYICREILRGLAHLHAHKVIHRDIKGQNVLLTENAEVKLVDFGVSAQLDR
TVGRRNTFIGTPYWMAPEVIACDENPDATYDYRSDIWSLGITAIEMAEGAPPLCDMHPMR
ALFLIPRNPPPRLKSKKWSKKFIDFIDTCLIKTYLSRPPTEQLLKFPFIRDQPTERQVRI
QLKDHIDRSRKKRGEKEETEYEYSGSEEEDDSHGEEGEPSSIMNVPGESTLRREFLRLQQ
ENKSNSEALKQQQQLQQQQQRDPEAHIKHLLHQRQRRIEEQKEERRRVEEQQRREREQRK
LQEKEQQRRLEDMQALRREEERRQAEREQEYKRKQLEEQRQSERLQRQLQQEHAYLKSLQ
QQQQQQQLQKQQQQQLLPGDRKPLYHYGRGMNPADKPAWAREVEERTRMNKQQNSPLAKS
KPGSTGPEPPIPQASPGPPGPLSQTPPMQRPVEPQEGPHKSLVAHRVPLKPYAAPVPRSQ
SLQDQPTRNLAAFPASHDPDPAIPAPTATPSARGAVIRQNSDPTSEGPGPSPNPPAWVRP
DNEAPPKVPQRTSSIATALNTSGAGGSRPAQAVRARPRSNSAWQIYLQRRAERGTPKPPG
PPAQPPGPPNASSNPDLRRSDPGWERSDSVLPASHGHLPQAGSLERNRVGVSSKPDSSPV
LSPGNKAKPDDHRSRPGRPADFVLLKERTLDEAPRPPKKAMDYSSSSEEVESSEDDEEEG
EGGPAEGSRDTPGGRSDGDTDSVSTMVVHDVEEITGTQPPYGGGTMVVQRTPEEERNLLH
ADSNGYTNLPDVVQPSHSPTENSKGQSPPSKDGSGDYQSRGLVKAPGKSSFTMFVDLGIY
QPGGSGDSIPITALVGGEGTRLDQLQYDVRKGSVVNVNPTNTRAHSETPEIRKYKKRFNS
EILCAALWGVNLLVGTENGLMLLDRSGQGKVYGLIGRRRFQQMDVLEGLNLLITISGKRN
KLRVYYLSWLRNKILHNDPEVEKKQGWTTVGDMEGCGHYRVVKYERIKFLVIALKSSVEV
YAWAPKPYHKFMAFKSFADLPHRPLLVDLTVEEGQRLKVIYGSSAGFHAVDVDSGNSYDI
YIPVHIQSQITPHAIIFLPNTDGMEMLLCYEDEGVYVNTYGRIIKDVVLQWGEMPTSVAY
ICSNQIMGWGEKAIEIRSVETGHLDGVFMHKRAQRLKFLCERNDKVFFASVRSGGSSQVY
FMTLNRNCIMNW
Function
Serine/threonine kinase which acts as a negative regulator of Ras-related Rap2-mediated signal transduction to control neuronal structure and AMPA receptor trafficking. Required for normal synaptic density, dendrite complexity, as well as surface AMPA receptor expression in hippocampal neurons. Can activate the JNK and MAPK14/p38 pathways and mediates stimulation of the stress-activated protein kinase MAPK14/p38 MAPK downstream of the Raf/ERK pathway. Phosphorylates: TANC1 upon stimulation by RAP2A, MBP and SMAD1. Has an essential function in negative selection of thymocytes, perhaps by coupling NCK1 to activation of JNK1.; Isoform 4 can activate the JNK pathway. Involved in the regulation of actin cytoskeleton reorganization, cell-matrix adhesion, cell-cell adhesion and cell migration.
Tissue Specificity
Expressed in the brain, isoform 2 is more abundant than isoform 1. Isoform 3 is ubiquitously expressed. Isoform 1 is most abundant in the skeletal muscle. Isoform 4 is ubiquitously expressed with relative high levels in brain, skeletal muscle, pancreas and testis.
Reactome Pathway
Oxidative Stress Induced Senescence (R-HSA-2559580 )

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Biomarker [1]
Atrial fibrillation DIS15W6U Strong Genetic Variation [2]
Cardiac disease DISVO1I5 Strong Genetic Variation [3]
Fibrosarcoma DISWX7MU Strong Biomarker [4]
Progressive supranuclear palsy DISO5KRQ Strong Genetic Variation [5]
Neoplasm DISZKGEW moderate Biomarker [6]
Autoimmune disease DISORMTM Limited Biomarker [7]
Long QT syndrome DISMKWS3 Limited Genetic Variation [8]
Nervous system inflammation DISB3X5A Limited Biomarker [7]
Osteoarthritis DIS05URM Limited Altered Expression [9]
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⏷ Show the Full List of 10 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 5 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Erythromycin DM4K7GQ Approved Misshapen-like kinase 1 (MINK1) increases the Torsade de pointes ADR of Erythromycin. [24]
Quinidine DMLPICK Approved Misshapen-like kinase 1 (MINK1) increases the Torsade de pointes ADR of Quinidine. [24]
Clarithromycin DM4M1SG Approved Misshapen-like kinase 1 (MINK1) increases the Torsade de pointes ADR of Clarithromycin. [24]
Cisapride DMY7PED Approved Misshapen-like kinase 1 (MINK1) increases the Torsade de pointes ADR of Cisapride. [24]
Terfenadine DM4KLPT Withdrawn from market Misshapen-like kinase 1 (MINK1) increases the Torsade de pointes ADR of Terfenadine. [24]
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4 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of Misshapen-like kinase 1 (MINK1). [10]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Misshapen-like kinase 1 (MINK1). [21]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Misshapen-like kinase 1 (MINK1). [22]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of Misshapen-like kinase 1 (MINK1). [21]
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10 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin increases the expression of Misshapen-like kinase 1 (MINK1). [11]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Misshapen-like kinase 1 (MINK1). [12]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Misshapen-like kinase 1 (MINK1). [13]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Misshapen-like kinase 1 (MINK1). [14]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Misshapen-like kinase 1 (MINK1). [15]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Misshapen-like kinase 1 (MINK1). [16]
Selenium DM25CGV Approved Selenium increases the expression of Misshapen-like kinase 1 (MINK1). [17]
Piroxicam DMTK234 Approved Piroxicam increases the expression of Misshapen-like kinase 1 (MINK1). [18]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Misshapen-like kinase 1 (MINK1). [20]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Misshapen-like kinase 1 (MINK1). [23]
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⏷ Show the Full List of 10 Drug(s)
1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
DNCB DMDTVYC Phase 2 DNCB affects the binding of Misshapen-like kinase 1 (MINK1). [19]
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References

1 Analysis of transcripts from 17p13.3 in medulloblastoma suggests ROX/MNT as a potential tumour suppressor gene.Eur J Cancer. 2004 Nov;40(16):2525-32. doi: 10.1016/j.ejca.2004.08.005.
2 MinK gene polymorphism in the pathogenesis of lone atrial fibrillation.Kardiol Pol. 2006 Nov;64(11):1205-11; discussion 1212-3.
3 MinK-KvLQT1 fusion proteins, evidence for multiple stoichiometries of the assembled IsK channel.J Biol Chem. 1998 Dec 18;273(51):34069-74. doi: 10.1074/jbc.273.51.34069.
4 Identification and functional characterization of a novel human misshapen/Nck interacting kinase-related kinase, hMINK beta.J Biol Chem. 2004 Dec 24;279(52):54387-97. doi: 10.1074/jbc.M404497200. Epub 2004 Oct 6.
5 Mutational study of the nuclear factor kappa B inducing kinase gene in patients with progressive supranuclear palsy.Neurosci Lett. 2003 Apr 10;340(2):158-60. doi: 10.1016/s0304-3940(03)00105-8.
6 Silencing of STRN4 suppresses the malignant characteristics of cancer cells.Cancer Sci. 2014 Dec;105(12):1526-32. doi: 10.1111/cas.12541. Epub 2014 Oct 23.
7 Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1.J Exp Med. 2017 May 1;214(5):1453-1469. doi: 10.1084/jem.20161120. Epub 2017 Apr 11.
8 A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype.J Mol Med (Berl). 2001 Sep;79(9):504-9. doi: 10.1007/s001090100249.
9 Dual roles of misshapen/NIK-related kinase (MINK1) in osteoarthritis subtypes through the activation of TGF signaling.Osteoarthritis Cartilage. 2020 Jan;28(1):112-121. doi: 10.1016/j.joca.2019.09.009. Epub 2019 Oct 21.
10 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
11 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
12 Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
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 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.
15 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
16 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
17 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
18 Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
19 Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
20 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.
21 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
22 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.
23 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
24 ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.