Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT78YN57)

• DOT Name: Angiopoietin-1 receptor (TEK)
• Synonyms: EC 2.7.10.1; Endothelial tyrosine kinase; Tunica interna endothelial cell kinase; Tyrosine kinase with Ig and EGF homology domains-2; Tyrosine-protein kinase receptor TEK; Tyrosine-protein kinase receptor TIE-2; hTIE2; p140 TEK; CD antigen CD202b
• Gene Name: TEK
• Related Disease:
  Multiple cutaneous and mucosal venous malformations
  TEK-related primary glaucoma
  Glaucoma 3, primary congenital, E
  Congenital glaucoma
• UniProt ID: TIE2_HUMAN
• PDB ID: 1FVR; 2GY5; 2GY7; 2OO8; 2OSC; 2P4I; 2WQB; 3BEA; 3L8P; 4K0V; 4X3J; 5MYA; 5MYB; 5UTK; 6MWE; 7E72
• EC Number: 2.7.10.1
• Pfam ID: PF00041 ; PF10430 ; PF07714
• Sequence:
  MDSLASLVLCGVSLLLSGTVEGAMDLILINSLPLVSDAETSLTCIASGWRPHEPITIGRD
  FEALMNQHQDPLEVTQDVTREWAKKVVWKREKASKINGAYFCEGRVRGEAIRIRTMKMRQ
  QASFLPATLTMTVDKGDNVNISFKKVLIKEEDAVIYKNGSFIHSVPRHEVPDILEVHLPH
  AQPQDAGVYSARYIGGNLFTSAFTRLIVRRCEAQKWGPECNHLCTACMNNGVCHEDTGEC
  ICPPGFMGRTCEKACELHTFGRTCKERCSGQEGCKSYVFCLPDPYGCSCATGWKGLQCNE
  ACHPGFYGPDCKLRCSCNNGEMCDRFQGCLCSPGWQGLQCEREGIQRMTPKIVDLPDHIE
  VNSGKFNPICKASGWPLPTNEEMTLVKPDGTVLHPKDFNHTDHFSVAIFTIHRILPPDSG
  VWVCSVNTVAGMVEKPFNISVKVLPKPLNAPNVIDTGHNFAVINISSEPYFGDGPIKSKK
  LLYKPVNHYEAWQHIQVTNEIVTLNYLEPRTEYELCVQLVRRGEGGEGHPGPVRRFTTAS
  IGLPPPRGLNLLPKSQTTLNLTWQPIFPSSEDDFYVEVERRSVQKSDQQNIKVPGNLTSV
  LLNNLHPREQYVVRARVNTKAQGEWSEDLTAWTLSDILPPQPENIKISNITHSSAVISWT
  ILDGYSISSITIRYKVQGKNEDQHVDVKIKNATITQYQLKGLEPETAYQVDIFAENNIGS
  SNPAFSHELVTLPESQAPADLGGGKMLLIAILGSAGMTCLTVLLAFLIILQLKRANVQRR
  MAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQDVIGEGNFGQVLK
  ARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNIINLLGACEHRGYLYL
  AIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQF
  IHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYTTNSD
  VWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKPLNCDDEVYDLMRQCWREKPY
  ERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDCSAEEAA
• Function: Tyrosine-protein kinase that acts as a cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of pro-inflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.
• Tissue Specificity: Detected in umbilical vein endothelial cells. Proteolytic processing gives rise to a soluble extracellular domain that is detected in blood plasma (at protein level). Predominantly expressed in endothelial cells and their progenitors, the angioblasts. Has been directly found in placenta and lung, with a lower level in umbilical vein endothelial cells, brain and kidney.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  HIF-1 sig.ling pathway (hsa04066)
  PI3K-Akt sig.ling pathway (hsa04151)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  Tie2 Signaling (R-HSA-210993)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple cutaneous and mucosal venous malformations	DISBRQNI	Definitive	Autosomal dominant	[1]
TEK-related primary glaucoma	DISJT7ID	Definitive	Autosomal dominant	[2]
Glaucoma 3, primary congenital, E	DIS21XDG	Strong	Autosomal dominant	[3]
Congenital glaucoma	DISHN3GO	Supportive	Autosomal dominant	[4]

15 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 Angiopoietin-1 receptor (TEK).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Angiopoietin-1 receptor (TEK).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Angiopoietin-1 receptor (TEK).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Angiopoietin-1 receptor (TEK).	[8]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Angiopoietin-1 receptor (TEK).	[9]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Angiopoietin-1 receptor (TEK).	[10]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Angiopoietin-1 receptor (TEK).	[11]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Angiopoietin-1 receptor (TEK).	[12]
Propranolol	DM79NTF	Approved	Propranolol decreases the expression of Angiopoietin-1 receptor (TEK).	[13]
Lenalidomide	DM6Q7U4	Approved	Lenalidomide decreases the expression of Angiopoietin-1 receptor (TEK).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Angiopoietin-1 receptor (TEK).	[16]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Angiopoietin-1 receptor (TEK).	[17]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Angiopoietin-1 receptor (TEK).	[19]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Angiopoietin-1 receptor (TEK).	[20]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of Angiopoietin-1 receptor (TEK).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of Angiopoietin-1 receptor (TEK).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Angiopoietin-1 receptor (TEK).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Angiopoietin-1 receptor (TEK).	[18]

References

• [1] Allelic and locus heterogeneity in inherited venous malformations. Hum Mol Genet. 1999 Jul;8(7):1279-89. doi: 10.1093/hmg/8.7.1279.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] A lymphatic defect causes ocular hypertension and glaucoma in mice. J Clin Invest. 2014 Oct;124(10):4320-4. doi: 10.1172/JCI77162. Epub 2014 Sep 9.
• [4] Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest. 2016 Jul 1;126(7):2575-87. doi: 10.1172/JCI85830. Epub 2016 Jun 6.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] 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.
• [8] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [9] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [10] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [11] Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells. Carcinogenesis. 2011 May;32(5):686-94. doi: 10.1093/carcin/bgr025. Epub 2011 Feb 10.
• [12] Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood. 2005 Apr 15;105(8):3286-94. doi: 10.1182/blood-2004-06-2101. Epub 2004 Dec 23.
• [13] Propranolol inhibits proliferation and induces apoptosis of hemangioma-derived endothelial cells via Akt pathway by down-regulating Ang-2 expression. Chem Biol Interact. 2020 Jan 25;316:108925. doi: 10.1016/j.cbi.2019.108925. Epub 2019 Dec 12.
• [14] Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
• [18] 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.
• [19] Non-nutritional sweeteners effects on endothelial vascular function. Toxicol In Vitro. 2020 Feb;62:104694. doi: 10.1016/j.tiv.2019.104694. Epub 2019 Oct 23.
• [20] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [21] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.