Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM8YMYT)

• DOT Name: Transcriptional enhancer factor TEF-4 (TEAD2)
• Synonyms: TEA domain family member 2; TEAD-2
• Gene Name: TEAD2
• Related Disease:
  Malignant glioma
  Polycystic ovarian syndrome
  Neuroendocrine cancer
  Multiple acyl-CoA dehydrogenase deficiency
  Neoplasm
  Neurofibromatosis type 2
• UniProt ID: TEAD2_HUMAN
• PDB ID: 3L15; 5DQ8; 5DQE; 5EMV; 5HGU; 6CDY; 6E5G; 6S60; 6S64; 6S66; 6S69; 6S6J; 6UYB; 6UYC; 6VAH; 7OYJ; 7T2J; 7T2K; 7T2L; 7T2M; 7TYP; 7TYQ; 7TYU; 8CUH; 8E1O; 8P29; 8POJ; 8POM; 8PON
• Pfam ID: PF01285 ; PF17725
• Sequence:
  MGEPRAGAALDDGSGWTGSEEGSEEGTGGSEGAGGDGGPDAEGVWSPDIEQSFQEALAIY
  PPCGRRKIILSDEGKMYGRNELIARYIKLRTGKTRTRKQVSSHIQVLARRKSREIQSKLK
  DQVSKDKAFQTMATMSSAQLISAPSLQAKLGPTGPQASELFQFWSGGSGPPWNVPDVKPF
  SQTPFTLSLTPPSTDLPGYEPPQALSPLPPPTPSPPAWQARGLGTARLQLVEFSAFVEPP
  DAVDSYQRHLFVHISQHCPSPGAPPLESVDVRQIYDKFPEKKGGLRELYDRGPPHAFFLV
  KFWADLNWGPSGEEAGAGGSISSGGFYGVSSQYESLEHMTLTCSSKVCSFGKQVVEKVET
  ERAQLEDGRFVYRLLRSPMCEYLVNFLHKLRQLPERYMMNSVLENFTILQVVTNRDTQEL
  LLCTAYVFEVSTSERGAQHHIYRLVRD
• Function: Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3'). May be involved in the gene regulation of neural development. Binds to the M-CAT motif.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway:
  RUNX3 regulates YAP1-mediated transcription (R-HSA-8951671)
  Formation of axial mesoderm (R-HSA-9796292)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malignant glioma	DISFXKOV	Strong	Biomarker	[1]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[2]
Neuroendocrine cancer	DISVGJET	moderate	Altered Expression	[3]
Multiple acyl-CoA dehydrogenase deficiency	DISEFBN7	Limited	Biomarker	[4]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[5]
Neurofibromatosis type 2	DISI8ECS	Limited	Altered Expression	[6]

10 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 Transcriptional enhancer factor TEF-4 (TEAD2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[16]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Transcriptional enhancer factor TEF-4 (TEAD2).	[17]

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 increases the methylation of Transcriptional enhancer factor TEF-4 (TEAD2).	[13]

References

• [1] IKBKE regulates cell proliferation and epithelial-mesenchymal transition of human malignant glioma via the Hippo pathway.Oncotarget. 2017 Jul 25;8(30):49502-49514. doi: 10.18632/oncotarget.17738.
• [2] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [3] SOX4, SOX11 and PAX6 mRNA expression was identified as a (prognostic) marker for the aggressiveness of neuroendocrine tumors of the lung by using next-generation expression analysis (NanoString).Future Oncol. 2015;11(7):1027-36. doi: 10.2217/fon.15.18.
• [4] Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable mature protein in a patient.Am J Hum Genet. 1991 Sep;49(3):575-80.
• [5] Identification of novel genes with somatic frameshift mutations within coding mononucleotide repeats in colorectal tumors with high microsatellite instability.Genes Chromosomes Cancer. 2003 Jan;36(1):48-56. doi: 10.1002/gcc.10141.
• [6] Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p.Biochim Biophys Acta. 2016 Apr;1859(4):599-611. doi: 10.1016/j.bbagrm.2016.02.010. Epub 2016 Feb 24.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.