Details of Drug Off-Target (DOT)

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

• DOT Name: Mitogen-activated protein kinase kinase kinase 7 (MAP3K7)
• Synonyms: EC 2.7.11.25; Transforming growth factor-beta-activated kinase 1; TGF-beta-activated kinase 1
• Gene Name: MAP3K7
• Related Disease:
  Cardiospondylocarpofacial syndrome
  Frontometaphyseal dysplasia
  Frontometaphyseal dysplasia 1
  Frontometaphyseal dysplasia 2
• UniProt ID: M3K7_HUMAN
• PDB ID: 2EVA; 2YIY; 4GS6; 4L3P; 4L52; 4L53; 4O91; 5E7R; 5GJD; 5GJF; 5GJG; 5J7S; 5J8I; 5J9L; 5JGA; 5JGB; 5JGD; 5JH6; 5JK3; 5V5N; 7NTH; 7NTI; 8GW3
• EC Number: 2.7.11.25
• Pfam ID: PF07714
• Sequence:
  MSTASAASSSSSSSAGEMIEAPSQVLNFEEIDYKEIEVEEVVGRGAFGVVCKAKWRAKDV
  AIKQIESESERKAFIVELRQLSRVNHPNIVKLYGACLNPVCLVMEYAEGGSLYNVLHGAE
  PLPYYTAAHAMSWCLQCSQGVAYLHSMQPKALIHRDLKPPNLLLVAGGTVLKICDFGTAC
  DIQTHMTNNKGSAAWMAPEVFEGSNYSEKCDVFSWGIILWEVITRRKPFDEIGGPAFRIM
  WAVHNGTRPPLIKNLPKPIESLMTRCWSKDPSQRPSMEEIVKIMTHLMRYFPGADEPLQY
  PCQYSDEGQSNSATSTGSFMDIASTNTSNKSDTNMEQVPATNDTIKRLESKLLKNQAKQQ
  SESGRLSLGASRGSSVESLPPTSEGKRMSADMSEIEARIAATTAYSKPKRGHRKTASFGN
  ILDVPEIVISGNGQPRRRSIQDLTVTGTEPGQVSSRSSSPSVRMITTSGPTSEKPTRSHP
  WTPDDSTDTNGSDNSIPMAYLTLDHQLQPLAPCPNSKESMAVFEQHCKMAQEYMKVQTEI
  ALLLQRKQELVAELDQDEKDQQNTSRLVQEHKKLLDENKSLSTYYQQCKKQLEVIRSQQQ
  KRQGTS
• Function: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs); both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1). Independently of MAP2Ks and p38 MAPKs, acts as a key activator of NF-kappa-B by promoting activation of the I-kappa-B-kinase (IKK) core complex. Mechanistically, recruited to polyubiquitin chains of RIPK2 and IKBKG/NEMO via TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3, and catalyzes phosphorylation and activation of IKBKB/IKKB component of the IKK complex, leading to NF-kappa-B activation. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity. Phosphorylates RIPK1 at 'Ser-321' which positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis. Phosphorylates STING1 in response to cGAMP-activation, promoting association between STEEP1 and STING1 and STING1 translocation to COPII vesicles.
• Tissue Specificity: Isoform 1A is the most abundant in ovary, skeletal muscle, spleen and blood mononuclear cells. Isoform 1B is highly expressed in brain, kidney and small intestine. Isoform 1C is the major form in prostate. Isoform 1D is the less abundant form.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Autophagy - animal (hsa04140)
  AMPK sig.ling pathway (hsa04152)
  Wnt sig.ling pathway (hsa04310)
  Osteoclast differentiation (hsa04380)
  Adherens junction (hsa04520)
  Neutrophil extracellular trap formation (hsa04613)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  IL-17 sig.ling pathway (hsa04657)
  T cell receptor sig.ling pathway (hsa04660)
  TNF sig.ling pathway (hsa04668)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  NOD1/2 Signaling Pathway (R-HSA-168638)
  Downstream TCR signaling (R-HSA-202424)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Ca2+ pathway (R-HSA-4086398)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Ub-specific processing proteases (R-HSA-5689880)
  TICAM1,TRAF6-dependent induction of TAK1 complex (R-HSA-9014325)
  Interleukin-1 signaling (R-HSA-9020702)
  IRAK2 mediated activation of TAK1 complex (R-HSA-937042)
  TRAF6-mediated induction of TAK1 complex within TLR4 complex (R-HSA-937072)
  Alpha-protein kinase 1 signaling pathway (R-HSA-9645460)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (R-HSA-975163)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiospondylocarpofacial syndrome	DISG0L91	Strong	Autosomal dominant	[1]
Frontometaphyseal dysplasia	DISXFPAW	Strong	Autosomal dominant	[2]
Frontometaphyseal dysplasia 1	DIS2MB3L	Strong	Autosomal dominant	[1]
Frontometaphyseal dysplasia 2	DISZN4TR	Strong	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Mitogen-activated protein kinase kinase kinase 7 (MAP3K7) decreases the response to substance of Camptothecin.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[18]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[6]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[9]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[5]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[10]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-49	DMTUC9E	Patented	PMID28870136-Compound-49 affects the binding of Mitogen-activated protein kinase kinase kinase 7 (MAP3K7).	[14]

References

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• [2] Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia. Am J Hum Genet. 2016 Aug 4;99(2):392-406. doi: 10.1016/j.ajhg.2016.05.024. Epub 2016 Jul 15.
• [3] 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.
• [4] 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.
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• [9] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [10] Ultradian cortisol pulsatility encodes a distinct, biologically important signal. PLoS One. 2011 Jan 18;6(1):e15766.
• [11] Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways. BMC Cancer. 2005 Jul 7;5:74. doi: 10.1186/1471-2407-5-74.
• [12] 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.
• [13] 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.
• [14] Implications of miRNAs on TGF-/TAK1/mTOR pathway in mediating the renoprotective effects of pentoxifylline against cisplatin-induced nephrotoxicity in rats. Toxicol Appl Pharmacol. 2020 Oct 1;404:115184. doi: 10.1016/j.taap.2020.115184. Epub 2020 Aug 7.
• [15] Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells. Environ Res. 2006 Jan;100(1):86-92.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] 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.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [20] Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study. Environ Health. 2014 Nov 13;13:94. doi: 10.1186/1476-069X-13-94.
• [21] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.