Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT91K3FC)

• DOT Name: Teneurin-4 (TENM4)
• Synonyms: Ten-4; Protein Odd Oz/ten-m homolog 4; Tenascin-M4; Ten-m4; Teneurin transmembrane protein 4
• Gene Name: TENM4
• Related Disease:
  Attention deficit hyperactivity disorder
  Bipolar depression
  Central nervous system lymphoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Essential tremor
  Major depressive disorder
  Ovarian cancer
  Ovarian neoplasm
  Psychotic disorder
  Tremor, hereditary essential, 5
  Acute myelogenous leukaemia
  Schizophrenia
  Gallbladder cancer
  Gallbladder carcinoma
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Bronchopulmonary dysplasia
  Colon cancer
  Colon carcinoma
  Lung carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Rectal carcinoma
• UniProt ID: TEN4_HUMAN
• PDB ID: 7BAM; 7BAN; 7BAO; 7PLP
• Pfam ID: PF07974 ; PF05593 ; PF06484 ; PF15636
• Sequence:
  MDVKERKPYRSLTRRRDAERRYTSSSADSEEGKAPQKSYSSSETLKAYDQDARLAYGSRV
  KDIVPQEAEEFCRTGANFTLRELGLEEVTPPHGTLYRTDIGLPHCGYSMGAGSDADMEAD
  TVLSPEHPVRLWGRSTRSGRSSCLSSRANSNLTLTDTEHENTETDHPGGLQNHARLRTPP
  PPLSHAHTPNQHHAASINSLNRGNFTPRSNPSPAPTDHSLSGEPPAGGAQEPAHAQENWL
  LNSNIPLETRNLGKQPFLGTLQDNLIEMDILGASRHDGAYSDGHFLFKPGGTSPLFCTTS
  PGYPLTSSTVYSPPPRPLPRSTFARPAFNLKKPSKYCNWKCAALSAIVISATLVILLAYF
  VAMHLFGLNWHLQPMEGQMYEITEDTASSWPVPTDVSLYPSGGTGLETPDRKGKGTTEGK
  PSSFFPEDSFIDSGEIDVGRRASQKIPPGTFWRSQVFIDHPVHLKFNVSLGKAALVGIYG
  RKGLPPSHTQFDFVELLDGRRLLTQEARSLEGTPRQSRGTVPPSSHETGFIQYLDSGIWH
  LAFYNDGKESEVVSFLTTAIESVDNCPSNCYGNGDCISGTCHCFLGFLGPDCGRASCPVL
  CSGNGQYMKGRCLCHSGWKGAECDVPTNQCIDVACSNHGTCITGTCICNPGYKGESCEEV
  DCMDPTCSGRGVCVRGECHCSVGWGGTNCETPRATCLDQCSGHGTFLPDTGLCSCDPSWT
  GHDCSIEICAADCGGHGVCVGGTCRCEDGWMGAACDQRACHPRCAEHGTCRDGKCECSPG
  WNGEHCTIAHYLDRVVKEGCPGLCNGNGRCTLDLNGWHCVCQLGWRGAGCDTSMETACGD
  SKDNDGDGLVDCMDPDCCLQPLCHINPLCLGSPNPLDIIQETQVPVSQQNLHSFYDRIKF
  LVGRDSTHIIPGENPFDGGHACVIRGQVMTSDGTPLVGVNISFVNNPLFGYTISRQDGSF
  DLVTNGGISIILRFERAPFITQEHTLWLPWDRFFVMETIIMRHEENEIPSCDLSNFARPN
  PVVSPSPLTSFASSCAEKGPIVPEIQALQEEISISGCKMRLSYLSSRTPGYKSVLRISLT
  HPTIPFNLMKVHLMVAVEGRLFRKWFAAAPDLSYYFIWDKTDVYNQKVFGLSEAFVSVGY
  EYESCPDLILWEKRTTVLQGYEIDASKLGGWSLDKHHALNIQSGILHKGNGENQFVSQQP
  PVIGSIMGNGRRRSISCPSCNGLADGNKLLAPVALTCGSDGSLYVGDFNYIRRIFPSGNV
  TNILELRNKDFRHSHSPAHKYYLATDPMSGAVFLSDSNSRRVFKIKSTVVVKDLVKNSEV
  VAGTGDQCLPFDDTRCGDGGKATEATLTNPRGITVDKFGLIYFVDGTMIRRIDQNGIIST
  LLGSNDLTSARPLSCDSVMDISQVHLEWPTDLAINPMDNSLYVLDNNVVLQISENHQVRI
  VAGRPMHCQVPGIDHFLLSKVAIHATLESATALAVSHNGVLYIAETDEKKINRIRQVTTS
  GEISLVAGAPSGCDCKNDANCDCFSGDDGYAKDAKLNTPSSLAVCADGELYVADLGNIRI
  RFIRKNKPFLNTQNMYELSSPIDQELYLFDTTGKHLYTQSLPTGDYLYNFTYTGDGDITL
  ITDNNGNMVNVRRDSTGMPLWLVVPDGQVYWVTMGTNSALKSVTTQGHELAMMTYHGNSG
  LLATKSNENGWTTFYEYDSFGRLTNVTFPTGQVSSFRSDTDSSVHVQVETSSKDDVTITT
  NLSASGAFYTLLQDQVRNSYYIGADGSLRLLLANGMEVALQTEPHLLAGTVNPTVGKRNV
  TLPIDNGLNLVEWRQRKEQARGQVTVFGRRLRVHNRNLLSLDFDRVTRTEKIYDDHRKFT
  LRILYDQAGRPSLWSPSSRLNGVNVTYSPGGYIAGIQRGIMSERMEYDQAGRITSRIFAD
  GKTWSYTYLEKSMVLLLHSQRQYIFEFDKNDRLSSVTMPNVARQTLETIRSVGYYRNIYQ
  PPEGNASVIQDFTEDGHLLHTFYLGTGRRVIYKYGKLSKLAETLYDTTKVSFTYDETAGM
  LKTINLQNEGFTCTIRYRQIGPLIDRQIFRFTEEGMVNARFDYNYDNSFRVTSMQAVINE
  TPLPIDLYRYDDVSGKTEQFGKFGVIYYDINQIITTAVMTHTKHFDAYGRMKEVQYEIFR
  SLMYWMTVQYDNMGRVVKKELKVGPYANTTRYSYEYDADGQLQTVSINDKPLWRYSYDLN
  GNLHLLSPGNSARLTPLRYDIRDRITRLGDVQYKMDEDGFLRQRGGDIFEYNSAGLLIKA
  YNRAGSWSVRYRYDGLGRRVSSKSSHSHHLQFFYADLTNPTKVTHLYNHSSSEITSLYYD
  LQGHLFAMELSSGDEFYIACDNIGTPLAVFSGTGLMIKQILYTAYGEIYMDTNPNFQIII
  GYHGGLYDPLTKLVHMGRRDYDVLAGRWTSPDHELWKHLSSSNVMPFNLYMFKNNNPISN
  SQDIKCFMTDVNSWLLTFGFQLHNVIPGYPKPDMDAMEPSYELIHTQMKTQEWDNSKSIL
  GVQCEVQKQLKAFVTLERFDQLYGSTITSCQQAPKTKKFASSGSVFGKGVKFALKDGRVT
  TDIISVANEDGRRVAAILNHAHYLENLHFTIDGVDTHYFVKPGPSEGDLAILGLSGGRRT
  LENGVNVTVSQINTVLNGRTRRYTDIQLQYGALCLNTRYGTTLDEEKARVLELARQRAVR
  QAWAREQQRLREGEEGLRAWTEGEKQQVLSTGRVQGYDGFFVISVEQYPELSDSANNIHF
  MRQSEMGRR
• Function: Involved in neural development, regulating the establishment of proper connectivity within the nervous system. Plays a role in the establishment of the anterior-posterior axis during gastrulation. Regulates the differentiation and cellular process formation of oligodendrocytes and myelination of small-diameter axons in the central nervous system (CNS). Promotes activation of focal adhesion kinase. May function as a cellular signal transducer.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[1]
Bipolar depression	DISA75FU	Strong	Biomarker	[2]
Central nervous system lymphoma	DISBYQTA	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Essential tremor	DIS7GBKQ	Strong	Biomarker	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[7]
Tremor, hereditary essential, 5	DIS7DKX0	Strong	Autosomal dominant	[8]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[9]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[10]
Gallbladder cancer	DISXJUAF	Disputed	Genetic Variation	[11]
Gallbladder carcinoma	DISD6ACL	Disputed	Genetic Variation	[11]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[12]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[5]
Bronchopulmonary dysplasia	DISO0BY5	Limited	Genetic Variation	[7]
Colon cancer	DISVC52G	Limited	Biomarker	[13]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[13]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[14]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[13]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[15]
Rectal carcinoma	DIS8FRR7	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Teneurin-4 (TENM4).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Teneurin-4 (TENM4).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Teneurin-4 (TENM4).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Teneurin-4 (TENM4).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Teneurin-4 (TENM4).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Teneurin-4 (TENM4).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Teneurin-4 (TENM4).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Teneurin-4 (TENM4).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Teneurin-4 (TENM4).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Teneurin-4 (TENM4).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Teneurin-4 (TENM4).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Teneurin-4 (TENM4).	[24]

References

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• [2] Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.Nat Genet. 2011 Sep 18;43(10):977-83. doi: 10.1038/ng.943.
• [3] The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing.Leukemia. 2015 Mar;29(3):677-85. doi: 10.1038/leu.2014.264. Epub 2014 Sep 5.
• [4] Expression and mechanism of microRNA-181A on incidence and survival in late liver metastases of colorectal cancer.Oncol Rep. 2016 Mar;35(3):1403-8. doi: 10.3892/or.2016.4546. Epub 2016 Jan 5.
• [5] Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer.PLoS One. 2017 May 4;12(5):e0177244. doi: 10.1371/journal.pone.0177244. eCollection 2017.
• [6] Teneurin transmembrane protein 4 is not a cause for essential tremor in a Canadian population.Mov Disord. 2017 Feb;32(2):292-295. doi: 10.1002/mds.26753. Epub 2017 Feb 3.
• [7] Replication of previous genome-wide association studies of psychiatric diseases in a large schizophrenia case-control sample from Spain.Schizophr Res. 2014 Oct;159(1):107-13. doi: 10.1016/j.schres.2014.07.004. Epub 2014 Aug 12.
• [8] Teneurin-4 is a novel regulator of oligodendrocyte differentiation and myelination of small-diameter axons in the CNS. J Neurosci. 2012 Aug 22;32(34):11586-99. doi: 10.1523/JNEUROSCI.2045-11.2012.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] Exome Sequencing Identifies TENM4 as a Novel Candidate Gene for Schizophrenia in the SCZD2 Locus at 11q14-21.Front Genet. 2019 Jan 28;9:725. doi: 10.3389/fgene.2018.00725. eCollection 2018.
• [11] Laparoscopy versus laparotomy approach of a radical resection for gallbladder cancer: a retrospective comparative study.Surg Endosc. 2020 Jul;34(7):2926-2938. doi: 10.1007/s00464-019-07075-4. Epub 2019 Aug 28.
• [12] A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.Mol Psychiatry. 2018 Mar;23(3):639-647. doi: 10.1038/mp.2016.259. Epub 2017 Jan 24.
• [13] Predictors of readmission and reoperation in patients with colorectal cancer.Support Care Cancer. 2020 May;28(5):2339-2350. doi: 10.1007/s00520-019-05050-2. Epub 2019 Sep 4.
• [14] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [15] Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population.Diabetologia. 2011 Dec;54(12):3071-7. doi: 10.1007/s00125-011-2293-3. Epub 2011 Sep 10.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] 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.
• [18] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [19] 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.
• [20] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [21] 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.
• [22] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [27] 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.