Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAUIPW0)

• DOT Name: Hyaluronan-binding protein 2 (HABP2)
• Synonyms: EC 3.4.21.-; Factor VII-activating protease; Factor seven-activating protease; FSAP; Hepatocyte growth factor activator-like protein; Plasma hyaluronan-binding protein
• Gene Name: HABP2
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Coronary atherosclerosis
  Coronary heart disease
  Venous thromboembolism
  Acute myocardial infarction
  Adenocarcinoma
  Adult respiratory distress syndrome
  Arteriosclerosis
  Atherosclerosis
  Hepatitis C virus infection
  Liver cirrhosis
  Medullary thyroid gland carcinoma
  Neoplasm
  Osteoarthritis
  Pulmonary fibrosis
  Schizophrenia
  Squamous cell carcinoma
  Stroke
  Thyroid cancer
  Thyroid gland carcinoma
  Type-1/2 diabetes
  Cardiovascular disease
  Thrombophilia
  Thyroid tumor
  Non-small-cell lung cancer
  Carotid stenosis
  Thyroid gland papillary carcinoma
• UniProt ID: HABP2_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF00008 ; PF00051 ; PF00089
• Sequence:
  MFARMSDLHVLLLMALVGKTACGFSLMSLLESLDPDWTPDQYDYSYEDYNQEENTSSTLT
  HAENPDWYYTEDQADPCQPNPCEHGGDCLVHGSTFTCSCLAPFSGNKCQKVQNTCKDNPC
  GRGQCLITQSPPYYRCVCKHPYTGPSCSQVVPVCRPNPCQNGATCSRHKRRSKFTCACPD
  QFKGKFCEIGSDDCYVGDGYSYRGKMNRTVNQHACLYWNSHLLLQENYNMFMEDAETHGI
  GEHNFCRNPDADEKPWCFIKVTNDKVKWEYCDVSACSAQDVAYPEESPTEPSTKLPGFDS
  CGKTEIAERKIKRIYGGFKSTAGKHPWQASLQSSLPLTISMPQGHFCGGALIHPCWVLTA
  AHCTDIKTRHLKVVLGDQDLKKEEFHEQSFRVEKIFKYSHYNERDEIPHNDIALLKLKPV
  DGHCALESKYVKTVCLPDGSFPSGSECHISGWGVTETGKGSRQLLDAKVKLIANTLCNSR
  QLYDHMIDDSMICAGNLQKPGQDTCQGDSGGPLTCEKDGTYYVYGIVSWGLECGKRPGVY
  TQVTKFLNWIKATIKSESGF
• Function: Cleaves the alpha-chain at multiple sites and the beta-chain between 'Lys-53' and 'Lys-54' but not the gamma-chain of fibrinogen and therefore does not initiate the formation of the fibrin clot and does not cause the fibrinolysis directly. It does not cleave (activate) prothrombin and plasminogen but converts the inactive single chain urinary plasminogen activator (pro-urokinase) to the active two chain form. Activates coagulation factor VII. May function as a tumor suppressor negatively regulating cell proliferation and cell migration.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Definitive	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Definitive	Genetic Variation	[2]
Coronary atherosclerosis	DISKNDYU	Definitive	Genetic Variation	[3]
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[3]
Venous thromboembolism	DISUR7CR	Definitive	Genetic Variation	[4]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[5]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[6]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[7]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[8]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[9]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[9]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Osteoarthritis	DIS05URM	Strong	Biomarker	[11]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[6]
Stroke	DISX6UHX	Strong	Genetic Variation	[13]
Thyroid cancer	DIS3VLDH	Strong	Genetic Variation	[1]
Thyroid gland carcinoma	DISMNGZ0	Strong	Genetic Variation	[1]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[9]
Cardiovascular disease	DIS2IQDX	moderate	Genetic Variation	[14]
Thrombophilia	DISQR7U7	moderate	Biomarker	[15]
Thyroid tumor	DISLVKMD	moderate	Genetic Variation	[1]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Altered Expression	[16]
Carotid stenosis	DISZA8D0	Limited	Genetic Variation	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[17]

2 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 Hyaluronan-binding protein 2 (HABP2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hyaluronan-binding protein 2 (HABP2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hyaluronan-binding protein 2 (HABP2).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hyaluronan-binding protein 2 (HABP2).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hyaluronan-binding protein 2 (HABP2).	[19]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Hyaluronan-binding protein 2 (HABP2).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Hyaluronan-binding protein 2 (HABP2).	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Hyaluronan-binding protein 2 (HABP2).	[24]

References

• [1] Segregation and expression analyses of hyaluronan-binding protein 2 (HABP2): insights from a large series of familial non-medullary thyroid cancers and literature review.Clin Endocrinol (Oxf). 2017 Jun;86(6):837-844. doi: 10.1111/cen.13316. Epub 2017 Mar 23.
• [2] Common genetic variation and novel loci associated with volumetric mammographic density.Breast Cancer Res. 2018 Apr 17;20(1):30. doi: 10.1186/s13058-018-0954-6.
• [3] Expression of the Marburg I Single Nucleotide Polymorphism (MI-SNP) and the Marburg II Single Nucleotide Polymorphism (MII-SNP) of the Factor VII-Activating Protease (FSAP) Gene and Risk of Coronary Artery Disease (CAD): A Pilot Study in a Single Population.Med Sci Monit. 2018 Jun 21;24:4271-4278. doi: 10.12659/MSM.906984.
• [4] Failure to validate association of gene polymorphisms in EPCR, PAR-1, FSAP and protein S Tokushima with venous thromboembolism among Californians of European ancestry.Thromb Haemost. 2008 Feb;99(2):453-5. doi: 10.1160/TH07-10-0607.
• [5] Interaction of factor VII activating protease (FSAP) with neutrophil extracellular traps (NETs).Thromb Res. 2018 Jan;161:36-42. doi: 10.1016/j.thromres.2017.11.012. Epub 2017 Nov 21.
• [6] Novel candidate tumor marker genes for lung adenocarcinoma.Oncogene. 2002 Oct 24;21(49):7598-604. doi: 10.1038/sj.onc.1205953.
• [7] Changes in factor VII-activating protease in a bleomycin-induced lung injury rat model and its influence on human pulmonary fibroblasts in vitro.Int J Mol Med. 2010 Oct;26(4):549-55. doi: 10.3892/ijmm_00000498.
• [8] Analysis of the substrate specificity of Factor VII activating protease (FSAP) and design of specific and sensitive peptide substrates.Thromb Haemost. 2017 Aug 30;117(9):1750-1760. doi: 10.1160/TH17-02-0081. Epub 2017 Jul 20.
• [9] The Marburg I variant (G534E) of the factor VII-activating protease determines liver fibrosis in hepatitis C infection by reduced proteolysis of platelet-derived growth factor BB.Hepatology. 2009 Mar;49(3):775-80. doi: 10.1002/hep.22707.
• [10] HABP2 Gene Mutations Do Not Cause Familial or Sporadic Non-Medullary Thyroid Cancer in a Highly Inbred Middle Eastern Population.Thyroid. 2016 May;26(5):667-71. doi: 10.1089/thy.2015.0537. Epub 2016 Apr 8.
• [11] Association study of candidate genes for susceptibility to Kashin-Beck disease in a Tibetan population.BMC Med Genet. 2017 Jun 26;18(1):69. doi: 10.1186/s12881-017-0423-6.
• [12] Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample.PLoS One. 2012;7(1):e29228. doi: 10.1371/journal.pone.0029228. Epub 2012 Jan 11.
• [13] Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells.Atherosclerosis. 2017 Oct;265:133-139. doi: 10.1016/j.atherosclerosis.2017.08.029. Epub 2017 Aug 25.
• [14] Role of glycine 221 in catalytic activity of hyaluronan-binding protein 2.J Biol Chem. 2017 Apr 14;292(15):6381-6388. doi: 10.1074/jbc.M116.757849. Epub 2017 Feb 27.
• [15] The G534E-polymorphism of the gene encoding the factor VII-activating protease is a risk factor for venous thrombosis and recurrent events.Thromb Res. 2012 Sep;130(3):441-4. doi: 10.1016/j.thromres.2012.02.009. Epub 2012 Mar 14.
• [16] Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non-small cell lung cancer.Oncol Rep. 2006 Nov;16(5):981-8.
• [17] Targeted next-generation sequencing in papillary thyroid carcinoma patients looking for germline variants predisposing to the disease.Endocrine. 2019 Jun;64(3):622-631. doi: 10.1007/s12020-019-01878-0. Epub 2019 Mar 2.
• [18] 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.
• [19] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [20] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [21] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.