Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT881M3K)

• DOT Name: Angiopoietin-4 (ANGPT4)
• Synonyms: ANG-4; Angiopoietin-3; ANG-3
• Gene Name: ANGPT4
• Related Disease:
  Glioma
  Adult glioblastoma
  Alzheimer disease
  Breast carcinoma
  Corneal neovascularization
  Fibrosarcoma
  Glioblastoma multiforme
  Metastatic malignant neoplasm
  Neoplasm
  Renal cell carcinoma
  Vascular dementia
  Vascular disease
  Cardiovascular disease
  Gastrointestinal stromal tumour
  Leiomyoma
  Schwannoma
  High blood pressure
  Osteoarthritis
  Stroke
• UniProt ID: ANGP4_HUMAN
• Pfam ID: PF00147
• Sequence:
  MLSQLAMLQGSLLLVVATMSVAQQTRQEADRGCETLVVQHGHCSYTFLLPKSEPCPPGPE
  VSRDSNTLQRESLANPLHLGKLPTQQVKQLEQALQNNTQWLKKLERAIKTILRSKLEQVQ
  QQMAQNQTAPMLELGTSLLNQTTAQIRKLTDMEAQLLNQTSRMDAQMPETFLSTNKLENQ
  LLLQRQKLQQLQGQNSALEKRLQALETKQQEELASILSKKAKLLNTLSRQSAALTNIERG
  LRGVRHNSSLLQDQQHSLRQLLVLLRHLVQERANASAPAFIMAGEQVFQDCAEIQRSGAS
  ASGVYTIQVSNATKPRKVFCDLQSSGGRWTLIQRRENGTVNFQRNWKDYKQGFGDPAGEH
  WLGNEVVHQLTRRAAYSLRVELQDWEGHEAYAQYEHFHLGSENQLYRLSVVGYSGSAGRQ
  SSLVLQNTSFSTLDSDNDHCLCKCAQVMSGGWWFDACGLSNLNGVYYHAPDNKYKMDGIR
  WHYFKGPSYSLRASRMMIRPLDI
• Function: Binds to TEK/TIE2, modulating ANGPT1 signaling. Can induce tyrosine phosphorylation of TEK/TIE2. Promotes endothelial cell survival, migration and angiogenesis.
• Tissue Specificity: Highly expressed in the lung with much lower levels found in other tissues.
• 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)
• Reactome Pathway: Tie2 Signaling (R-HSA-210993)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Corneal neovascularization	DISKOGZP	Strong	Biomarker	[5]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[7]
Vascular dementia	DISVO82H	Strong	Genetic Variation	[8]
Vascular disease	DISVS67S	Strong	Genetic Variation	[8]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[9]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[10]
Leiomyoma	DISLDDFN	moderate	Altered Expression	[10]
Schwannoma	DISTTVLA	moderate	Altered Expression	[10]
High blood pressure	DISY2OHH	Limited	Biomarker	[11]
Osteoarthritis	DIS05URM	Limited	Biomarker	[12]
Stroke	DISX6UHX	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Angiopoietin-4 (ANGPT4).	[14]

2 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 Angiopoietin-4 (ANGPT4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Angiopoietin-4 (ANGPT4).	[16]

References

• [1] Construction of a ganciclovir-sensitive lentiviral vector to assess the influence of angiopoietin-3 and soluble Tie2 on glioma growth.J Neurooncol. 2010 Aug;99(1):1-11. doi: 10.1007/s11060-009-0095-y. Epub 2009 Dec 18.
• [2] Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis.Cancer Res. 2010 Sep 15;70(18):7283-93. doi: 10.1158/0008-5472.CAN-09-4125. Epub 2010 Sep 7.
• [3] Angiotensin-III is Increased in Alzheimer's Disease in Association with Amyloid- and Tau Pathology.J Alzheimers Dis. 2017;58(1):203-214. doi: 10.3233/JAD-161265.
• [4] Angiopoietin-3 inhibits pulmonary metastasis by inhibiting tumor angiogenesis.Cancer Res. 2004 Sep 1;64(17):6119-26. doi: 10.1158/0008-5472.CAN-04-1054.
• [5] Biological characterization of angiopoietin-3 and angiopoietin-4.FASEB J. 2004 Aug;18(11):1200-8. doi: 10.1096/fj.03-1466com.
• [6] Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation.FASEB J. 2015 Sep;29(9):3668-77. doi: 10.1096/fj.14-268920. Epub 2015 May 14.
• [7] Expression of the angiopoietins and their receptor Tie2 in human renal clear cell carcinomas; regulation by the von Hippel-Lindau gene and hypoxia.J Pathol. 2002 Dec;198(4):502-10. doi: 10.1002/path.1228.
• [8] Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia.J Hum Genet. 2010 Oct;55(10):649-55. doi: 10.1038/jhg.2010.79. Epub 2010 Jul 1.
• [9] Effects of angiotensin III on c-Jun N terminal kinase in Wistar and hypertensive rat vascular smooth muscle cells.Peptides. 2020 Jan;123:170204. doi: 10.1016/j.peptides.2019.170204. Epub 2019 Nov 15.
• [10] Expression of angiopoietin-1, 2 and 4 and Tie-1 and 2 in gastrointestinal stromal tumor, leiomyoma and schwannoma.World J Gastroenterol. 2007 Sep 7;13(33):4473-9. doi: 10.3748/wjg.v13.i33.4473.
• [11] Evolution of a New Class of Antihypertensive Drugs: Targeting the Brain Renin-Angiotensin System.Hypertension. 2020 Jan;75(1):6-15. doi: 10.1161/HYPERTENSIONAHA.119.12675. Epub 2019 Dec 2.
• [12] Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment.J Biomed Mater Res B Appl Biomater. 2020 Jan;108(1):234-242. doi: 10.1002/jbm.b.34383. Epub 2019 Apr 8.
• [13] Revisiting the Brain Renin-Angiotensin System-Focus on Novel Therapies.Curr Hypertens Rep. 2019 Apr 4;21(4):28. doi: 10.1007/s11906-019-0937-8.
• [14] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [15] 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.
• [16] 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.