Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0ALMEG)

• DOT Name: Mitogen-activated protein kinase kinase kinase 20 (MAP3K20)
• Synonyms: EC 2.7.11.25; Human cervical cancer suppressor gene 4 protein; HCCS-4; Leucine zipper- and sterile alpha motif-containing kinase; MLK-like mitogen-activated protein triple kinase; Mitogen-activated protein kinase kinase kinase MLT; Mixed lineage kinase 7; Mixed lineage kinase-related kinase; MLK-related kinase; MRK; Sterile alpha motif- and leucine zipper-containing kinase AZK
• Gene Name: MAP3K20
• Related Disease:
  Myopathy, centronuclear, 6, with fiber-type disproportion
  Congenital fiber-type disproportion myopathy
  Split-foot malformation-mesoaxial polydactyly syndrome
• UniProt ID: M3K20_HUMAN
• PDB ID: 5HES; 5X5O; 6JUT; 6JUU; 7YAW; 7YAZ
• EC Number: 2.7.11.25
• Pfam ID: PF07714 ; PF00536
• Sequence:
  MSSLGASFVQIKFDDLQFFENCGGGSFGSVYRAKWISQDKEVAVKKLLKIEKEAEILSVL
  SHRNIIQFYGVILEPPNYGIVTEYASLGSLYDYINSNRSEEMDMDHIMTWATDVAKGMHY
  LHMEAPVKVIHRDLKSRNVVIAADGVLKICDFGASRFHNHTTHMSLVGTFPWMAPEVIQS
  LPVSETCDTYSYGVVLWEMLTREVPFKGLEGLQVAWLVVEKNERLTIPSSCPRSFAELLH
  QCWEADAKKRPSFKQIISILESMSNDTSLPDKCNSFLHNKAEWRCEIEATLERLKKLERD
  LSFKEQELKERERRLKMWEQKLTEQSNTPLLPSFEIGAWTEDDVYCWVQQLVRKGDSSAE
  MSVYASLFKENNITGKRLLLLEEEDLKDMGIVSKGHIIHFKSAIEKLTHDYINLFHFPPL
  IKDSGGEPEENEEKIVNLELVFGFHLKPGTGPQDCKWKMYMEMDGDEIAITYIKDVTFNT
  NLPDAEILKMTKPPFVMEKWIVGIAKSQTVECTVTYESDVRTPKSTKHVHSIQWSRTKPQ
  DEVKAVQLAIQTLFTNSDGNPGSRSDSSADCQWLDTLRMRQIASNTSLQRSQSNPILGSP
  FFSHFDGQDSYAAAVRRPQVPIKYQQITPVNQSRSSSPTQYGLTKNFSSLHLNSRDSGFS
  SGNTDTSSERGRYSDRSRNKYGRGSISLNSSPRGRYSGKSQHSTPSRGRYPGKFYRVSQS
  ALNPHQSPDFKRSPRDLHQPNTIPGMPLHPETDSRASEEDSKVSEGGWTKVEYRKKPHRP
  SPAKTNKERARGDHRGWRNF
• Function: Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation. Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways. Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6. Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress. May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 ; [Isoform ZAKalpha]: Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation. Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes. Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively. Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death. Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha. Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis. NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20. Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) ; [Isoform ZAKbeta]: Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress. May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha.
• Tissue Specificity: Ubiquitously expressed. Isoform ZAKbeta is the predominant form in all tissues examined, except for liver, in which isoform ZAKalpha is more highly expressed.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopathy, centronuclear, 6, with fiber-type disproportion	DIS7WBOO	Moderate	Autosomal recessive	[1]
Congenital fiber-type disproportion myopathy	DISU9T2M	Supportive	Autosomal dominant	[2]
Split-foot malformation-mesoaxial polydactyly syndrome	DIS3JCKA	Limited	Autosomal recessive	[3]

17 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 20 (MAP3K20).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[18]
3,7,3',4'-TETRAHYDROXYFLAVONE	DMES906	Investigative	3,7,3',4'-TETRAHYDROXYFLAVONE increases the expression of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[19]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dasatinib	DMJV2EK	Approved	Dasatinib affects the binding of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mitogen-activated protein kinase kinase kinase 20 (MAP3K20).	[17]

References

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• [2] Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion. Brain. 2017 Jan;140(1):37-48. doi: 10.1093/brain/aww257. Epub 2016 Nov 5.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] 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.
• [7] Doxorubicin induces ZAK overexpression with a subsequent enhancement of apoptosis and attenuation of survivability in human osteosarcoma cells. Environ Toxicol. 2018 Feb;33(2):191-197. doi: 10.1002/tox.22507. Epub 2017 Nov 6.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [10] 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.
• [11] 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.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [15] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Fisetin activates Hippo pathway and JNK/ERK/AP-1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression. Environ Toxicol. 2019 Aug;34(8):902-911. doi: 10.1002/tox.22761. Epub 2019 May 1.