Details of Drug Off-Target (DOT)

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

• DOT Name: Histidine-rich glycoprotein (HRG)
• Synonyms: Histidine-proline-rich glycoprotein; HPRG
• Gene Name: HRG
• Related Disease:
  Coronary heart disease
  Myocardial infarction
  Rheumatoid arthritis
  Adult glioblastoma
  Adult respiratory distress syndrome
  Bacterial infection
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Central nervous system neoplasm
  Cerebral infarction
  Colorectal carcinoma
  Glioblastoma multiforme
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency
  Herpes simplex infection
  Homocystinuria
  Lung cancer
  Lung carcinoma
  Male infertility
  Malignant glioma
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-small-cell lung cancer
  Pancreatitis
  Pneumonia
  Pneumonitis
  Skin neoplasm
  Thrombophilia
  Advanced cancer
  Breast neoplasm
  Rhabdomyosarcoma
  Fetal growth restriction
  Invasive breast carcinoma
• UniProt ID: HRG_HUMAN
• Pfam ID: PF00031
• Sequence:
  MKALIAALLLITLQYSCAVSPTDCSAVEPEAEKALDLINKRRRDGYLFQLLRIADAHLDR
  VENTTVYYLVLDVQESDCSVLSRKYWNDCEPPDSRRPSEIVIGQCKVIATRHSHESQDLR
  VIDFNCTTSSVSSALANTKDSPVLIDFFEDTERYRKQANKALEKYKEENDDFASFRVDRI
  ERVARVRGGEGTGYFVDFSVRNCPRHHFPRHPNVFGFCRADLFYDVEALDLESPKNLVIN
  CEVFDPQEHENINGVPPHLGHPFHWGGHERSSTTKPPFKPHGSRDHHHPHKPHEHGPPPP
  PDERDHSHGPPLPQGPPPLLPMSCSSCQHATFGTNGAQRHSHNNNSSDLHPHKHHSHEQH
  PHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHHPHCHDFQDYGPCDPP
  PHNQGHCCHGHGPPPGHLRRRGPGKGPRPFHCRQIGSVYRLPPLRKGEVLPLPEANFPSF
  PLPHHKHPLKPDNQPFPQSVSESCPGKFKSGFPQVSMFFTHTFPK
• Function: Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis.
• Tissue Specificity: Expressed in macrophages and in malignant cells. Expressed by the liver and secreted in plasma (at protein level).
• Reactome Pathway:
  Dissolution of Fibrin Clot (R-HSA-75205)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[5]
Bacterial infection	DIS5QJ9S	Strong	Biomarker	[6]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[8]
Cerebral infarction	DISR1WNP	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	DIS0AUHL	Strong	Autosomal dominant	[13]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[14]
Homocystinuria	DISK3N1S	Strong	Biomarker	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[17]
Malignant glioma	DISFXKOV	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[18]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[18]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[5]
Pneumonia	DIS8EF3M	Strong	Biomarker	[5]
Pneumonitis	DIS88E0K	Strong	Biomarker	[5]
Skin neoplasm	DIS16DDV	Strong	Genetic Variation	[20]
Thrombophilia	DISQR7U7	Strong	Biomarker	[15]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[21]
Breast neoplasm	DISNGJLM	moderate	Biomarker	[22]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[23]
Fetal growth restriction	DIS5WEJ5	Limited	Altered Expression	[24]
Invasive breast carcinoma	DISANYTW	Limited	Biomarker	[25]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID27977313-Compound-29	DMIF7KG	Patented	Histidine-rich glycoprotein (HRG) increases the Haemorrhagic diathesis ADR of PMID27977313-Compound-29.	[38]

3 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 Histidine-rich glycoprotein (HRG).	[26]
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the phosphorylation of Histidine-rich glycoprotein (HRG).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histidine-rich glycoprotein (HRG).	[37]

10 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 Histidine-rich glycoprotein (HRG).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histidine-rich glycoprotein (HRG).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histidine-rich glycoprotein (HRG).	[27]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Histidine-rich glycoprotein (HRG).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histidine-rich glycoprotein (HRG).	[30]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Histidine-rich glycoprotein (HRG).	[31]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Histidine-rich glycoprotein (HRG).	[32]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Histidine-rich glycoprotein (HRG).	[33]
Acocantherin	DM7JT24	Approved	Acocantherin affects the expression of Histidine-rich glycoprotein (HRG).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histidine-rich glycoprotein (HRG).	[36]

References

• [1] Novel protein biomarkers associated with coronary artery disease in statin-treated patients with familial hypercholesterolemia.J Clin Lipidol. 2017 May-Jun;11(3):682-693. doi: 10.1016/j.jacl.2017.03.014. Epub 2017 Apr 4.
• [2] The histidin-rich glycoprotein Pro186/Ser polymorphism is not related to myocardial infarction in the ECTIM study.Thromb Haemost. 1998 Feb;79(2):359-61.
• [3] Proteomics analysis reveals differential pattern of widespread protein expression and novel role of histidine-rich glycoprotein and lipopolysaccharide-binding protein in rheumatoid arthritis.Int J Biol Macromol. 2018 Apr 1;109:704-710. doi: 10.1016/j.ijbiomac.2017.12.075. Epub 2017 Dec 13.
• [4] Histidine-rich glycoprotein can prevent development of mouse experimental glioblastoma.PLoS One. 2009 Dec 31;4(12):e8536. doi: 10.1371/journal.pone.0008536.
• [5] Histidine-Rich Glycoprotein Suppresses Hyperinflammatory Responses of Lung in a Severe Acute Pancreatitis Mouse Model.Pancreas. 2018 Oct;47(9):1156-1164. doi: 10.1097/MPA.0000000000001153.
• [6] Histidine-rich glycoprotein promotes bacterial entrapment in clots and decreases mortality in a mouse model of sepsis.Blood. 2010 Sep 30;116(13):2365-72. doi: 10.1182/blood-2010-02-271858. Epub 2010 Jun 29.
• [7] Progesterone impairs Herceptin effect on breast cancer cells.Oncol Lett. 2018 Feb;15(2):1817-1822. doi: 10.3892/ol.2017.7493. Epub 2017 Nov 27.
• [8] Leukocyte Differentiation by Histidine-Rich Glycoprotein/Stanniocalcin-2 Complex Regulates Murine Glioma Growth through Modulation of Antitumor Immunity.Mol Cancer Ther. 2018 Sep;17(9):1961-1972. doi: 10.1158/1535-7163.MCT-18-0097. Epub 2018 Jun 26.
• [9] Prothrombotic risk factors in childhood stroke and venous thrombosis.Eur J Pediatr. 1999 Dec;158 Suppl 3:S117-21. doi: 10.1007/pl00014333.
• [10] HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer.Oncogene. 2017 Apr 27;36(17):2394-2404. doi: 10.1038/onc.2016.390. Epub 2016 Dec 12.
• [11] High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck.PLoS One. 2013;8(2):e56765. doi: 10.1371/journal.pone.0056765. Epub 2013 Feb 28.
• [12] Histidine-rich glycoprotein function in hepatocellular carcinoma depends on its N-glycosylation status, and it regulates cell proliferation by inhibiting Erk1/2 phosphorylation.Oncotarget. 2015 Oct 6;6(30):30222-31. doi: 10.18632/oncotarget.4997.
• [13] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [14] Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner.J Virol. 2019 Feb 5;93(4):e01749-18. doi: 10.1128/JVI.01749-18. Print 2019 Feb 15.
• [15] Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group.Eur J Pediatr. 1999 Dec;158 Suppl 3:S97-104. doi: 10.1007/pl00014359.
• [16] Decreased Levels of Histidine-Rich Glycoprotein in Advanced Lung Cancer: Association with Prothrombotic Alterations.Dis Markers. 2019 Mar 3;2019:8170759. doi: 10.1155/2019/8170759. eCollection 2019.
• [17] The effect of a specific histidine-rich glycoprotein polymorphism on male infertility and semen parameters.Reprod Biomed Online. 2016 Aug;33(2):180-8. doi: 10.1016/j.rbmo.2016.05.004. Epub 2016 May 16.
• [18] Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer.Oncologist. 2019 Aug;24(8):1095-1102. doi: 10.1634/theoncologist.2018-0695. Epub 2019 Apr 11.
• [19] Hypoxia-inducible factor 2 drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine-rich glycoprotein.Hepatology. 2018 Jun;67(6):2196-2214. doi: 10.1002/hep.29754. Epub 2018 Apr 19.
• [20] Identification of Fetuin-B as a member of a cystatin-like gene family on mouse chromosome 16 with tumor suppressor activity.Genome. 2004 Oct;47(5):931-46. doi: 10.1139/g04-043.
• [21] Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with 2 integrin.Matrix Biol. 2015 Oct;48:89-99. doi: 10.1016/j.matbio.2015.06.002. Epub 2015 Jun 5.
• [22] Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer.BMC Med Genomics. 2009 Jun 24;2:37. doi: 10.1186/1755-8794-2-37.
• [23] Evidence that muscle cells do not express the histidine-rich glycoprotein associated with AMP deaminase but can internalise the plasma protein.Eur J Histochem. 2011 Feb 25;55(1):e6. doi: 10.4081/ejh.2011.e6.
• [24] Combination of serum histidine-rich glycoprotein and uterine artery Doppler to predict preeclampsia.Hypertens Res. 2018 Apr;41(4):275-281. doi: 10.1038/s41440-018-0013-9. Epub 2018 Feb 7.
• [25] Co-expression of ErbB-family members in human breast cancer: Her-2/neu is the preferred dimerization candidate in nodal-positive tumors.Breast Cancer Res Treat. 2003 Aug;80(3):353-61. doi: 10.1023/A:1024929522376.
• [26] 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.
• [27] 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.
• [28] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [29] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [30] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [31] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [32] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [33] Estrogens reduce plasma histidine-rich glycoprotein (HRG) levels in a dose-dependent way. Thromb Haemost. 1995 Mar;73(3):484-7.
• [34] Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull. 2007 Feb;30(2):247-53. doi: 10.1248/bpb.30.247.
• [35] Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. Proteomics Clin Appl. 2015 Oct;9(9-10):907-16. doi: 10.1002/prca.201400148. Epub 2015 May 15.
• [36] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [37] 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.
• [38] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.