Details of Drug Off-Target (DOT)

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

DOT Name	Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS)
Synonyms	Hrs; Protein pp110
Gene Name	HGS
Related Disease	Adenoma ( ) Allergic rhinitis ( ) Alzheimer disease ( ) Arrhythmia ( ) Atrial fibrillation ( ) Breast neoplasm ( ) Brugada syndrome ( ) Cardiac failure ( ) Cardiomyopathy ( ) Cardiovascular disease ( ) Classic Hodgkin lymphoma ( ) Colon carcinoma ( ) Congestive heart failure ( ) Dementia ( ) Depression ( ) Diabetic macular edema ( ) Familial long QT syndrome ( ) Hepatitis C virus infection ( ) Hepatocellular carcinoma ( ) Liver cancer ( ) Liver cirrhosis ( ) Myositis disease ( ) Neoplasm ( ) Non-insulin dependent diabetes ( ) Peripheral arterial disease ( ) Schwannoma ( ) Triple negative breast cancer ( ) Advanced cancer ( ) Age-related macular degeneration ( ) Alcohol dependence ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Breast cancer ( ) Breast carcinoma ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Colorectal carcinoma ( ) Epithelial ovarian cancer ( ) Generalized anxiety disorder ( ) High blood pressure ( ) Nervous system disease ( ) Neuroblastoma ( ) Neurofibromatosis type 2 ( ) Post-traumatic stress disorder ( ) Type-1 diabetes ( ) Type-1/2 diabetes ( )
UniProt ID	HGS_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2D3G; 3F1I; 3OBQ; 3ZYQ; 4AVX
Pfam ID	PF01363 ; PF12210 ; PF00790
Sequence	MGRGSGTFERLLDKATSQLLLETDWESILQICDLIRQGDTQAKYAVNSIKKKVNDKNPHV ALYALEVMESVVKNCGQTVHDEVANKQTMEELKDLLKRQVEVNVRNKILYLIQAWAHAFR NEPKYKVVQDTYQIMKVEGHVFPEFKESDAMFAAERAPDWVDAEECHRCRVQFGVMTRKH HCRACGQIFCGKCSSKYSTIPKFGIEKEVRVCEPCYEQLNRKAEGKATSTTELPPEYLTS PLSQQSQLPPKRDETALQEEEELQLALALSQSEAEEKERLRQKSTYTSYPKAEPMPSASS APPASSLYSSPVNSSAPLAEDIDPELARYLNRNYWEKKQEEARKSPTPSAPVPLTEPAAQ PGEGHAAPTNVVENPLPETDSQPIPPSGGPFSEPQFHNGESEESHEQFLKALQNAVTTFV NRMKSNHMRGRSITNDSAVLSLFQSINGMHPQLLELLNQLDERRLYYEGLQDKLAQIRDA RGALSALREEHREKLRRAAEEAERQRQIQLAQKLEIMRQKKQEYLEVQRQLAIQRLQEQE KERQMRLEQQKQTVQMRAQMPAFPLPYAQLQAMPAAGGVLYQPSGPASFPSTFSPAGSVE GSPMHGVYMSQPAPAAGPYPSMPSTAADPSMVSAYMYPAGATGAQAAPQAQAGPTASPAY SSYQPTPTAGYQNVASQAPQSLPAISQPPQSSTMGYMGSQSVSMGYQPYNMQNLMTTLPS QDASLPPQQPYIAGQQPMYQQMAPSGGPPQQQPPVAQQPQAQGPPAQGSEAQLISFD
Function	Involved in intracellular signal transduction mediated by cytokines and growth factors. When associated with STAM, it suppresses DNA signaling upon stimulation by IL-2 and GM-CSF. Could be a direct effector of PI3-kinase in vesicular pathway via early endosomes and may regulate trafficking to early and late endosomes by recruiting clathrin. May concentrate ubiquitinated receptors within clathrin-coated regions. Involved in down-regulation of receptor tyrosine kinase via multivesicular body (MVBs) when complexed with STAM (ESCRT-0 complex). The ESCRT-0 complex binds ubiquitin and acts as a sorting machinery that recognizes ubiquitinated receptors and transfers them to further sequential lysosomal sorting/trafficking processes. May contribute to the efficient recruitment of SMADs to the activin receptor complex. Involved in receptor recycling via its association with the CART complex, a multiprotein complex required for efficient transferrin receptor recycling but not for EGFR degradation.
Tissue Specificity	Ubiquitous expression in adult and fetal tissues with higher expression in testis and peripheral blood leukocytes.
KEGG Pathway	Viral life cycle - HIV-1 (hsa03250 ) Endocytosis (hsa04144 ) Phagosome (hsa04145 )
Reactome Pathway	Lysosome Vesicle Biogenesis (R-HSA-432720 ) Ub-specific processing proteases (R-HSA-5689880 ) Negative regulation of MET activity (R-HSA-6807004 ) Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825 ) Clathrin-mediated endocytosis (R-HSA-8856828 ) InlB-mediated entry of Listeria monocytogenes into host cell (R-HSA-8875360 ) RHOU GTPase cycle (R-HSA-9013420 ) Endosomal Sorting Complex Required For Transport (ESCRT) (R-HSA-917729 ) Inhibition of membrane repair (R-HSA-9635644 ) Prevention of phagosomal-lysosomal fusion (R-HSA-9636383 ) RHOBTB3 ATPase cycle (R-HSA-9706019 ) EGFR downregulation (R-HSA-182971 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Allergic rhinitis	DIS3U9HN	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Arrhythmia	DISFF2NI	Strong	Altered Expression	[4]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Brugada syndrome	DISSGN0E	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[9]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[10]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Dementia	DISXL1WY	Strong	Genetic Variation	[3]
Depression	DIS3XJ69	Strong	Biomarker	[13]
Diabetic macular edema	DIS162FN	Strong	Biomarker	[14]
Familial long QT syndrome	DISRNNCY	Strong	Biomarker	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Liver cancer	DISDE4BI	Strong	Biomarker	[16]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[17]
Myositis disease	DISCIXF0	Strong	Biomarker	[18]
Neoplasm	DISZKGEW	Strong	Altered Expression	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[20]
Peripheral arterial disease	DIS78WFB	Strong	Biomarker	[21]
Schwannoma	DISTTVLA	Strong	Altered Expression	[22]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[23]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[24]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[25]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[26]
Arteriosclerosis	DISK5QGC	moderate	Genetic Variation	[25]
Atherosclerosis	DISMN9J3	moderate	Genetic Variation	[25]
Breast cancer	DIS7DPX1	Limited	Biomarker	[27]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[27]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[16]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[28]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[29]
Generalized anxiety disorder	DISPSQCW	Limited	Biomarker	[30]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[31]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[32]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[33]
Neurofibromatosis type 2	DISI8ECS	Limited	Biomarker	[34]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[35]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[36]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[37]
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⏷ Show the Full List of 45 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) affects the response to substance of Methotrexate.	[49]
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4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[46]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[48]
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7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[40]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[41]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[42]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[43]
Selenium	DM25CGV	Approved	Selenium increases the expression of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[44]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the expression of Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS).	[45]
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⏷ Show the Full List of 7 Drug(s)

References

1	Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) and guanylate kinase 1 (GUK1) are differentially expressed in GH-secreting adenomas.Pituitary. 2006;9(2):83-92. doi: 10.1007/s11102-006-9277-1.
2	Hydrogen-rich saline attenuates eosinophil activation in a guinea pig model of allergic rhinitis via reducing oxidative stress.J Inflamm (Lond). 2017 Jan 13;14:1. doi: 10.1186/s12950-016-0148-x. eCollection 2017.
3	Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses.Alzheimers Dement. 2015 Dec;11(12):1439-1451. doi: 10.1016/j.jalz.2015.05.015. Epub 2015 Jun 12.
4	Arrhythmias in congenital heart disease: a position paper of the European Heart Rhythm Association (EHRA), Association for European Paediatric and Congenital Cardiology (AEPC), and the European Society of Cardiology (ESC) Working Group on Grown-up Congenital heart disease, endorsed by HRS, PACES, APHRS, and SOLAECE.Europace. 2018 Nov 1;20(11):1719-1753. doi: 10.1093/europace/eux380.
5	Oral anticoagulant therapy in adults with congenital heart disease and atrial arrhythmias: Implementation of guidelines.Int J Cardiol. 2018 Apr 15;257:67-74. doi: 10.1016/j.ijcard.2017.12.038.
6	Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) interacts with PELP1 and activates MAPK.J Biol Chem. 2006 Feb 17;281(7):4395-403. doi: 10.1074/jbc.M510368200. Epub 2005 Dec 12.
7	Update of diagnosis and management of inherited cardiac arrhythmias.Circ J. 2013;77(12):2867-72. doi: 10.1253/circj.cj-13-1217. Epub 2013 Nov 7.
8	Relationship Between Handgrip Strength and Length of Stay for Left Ventricular Assist Device Implantation.Nutr Clin Pract. 2017 Feb;32(1):98-102. doi: 10.1177/0884533616665926. Epub 2016 Sep 25.
9	2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: Executive summary.Heart Rhythm. 2019 Nov;16(11):e373-e407. doi: 10.1016/j.hrthm.2019.09.019.
10	Associations Between Measures of Sarcopenic Obesity and Risk of Cardiovascular Disease and Mortality: A Cohort Study and Mendelian Randomization Analysis Using the UK Biobank.J Am Heart Assoc. 2019 Jul 2;8(13):e011638. doi: 10.1161/JAHA.118.011638. Epub 2019 Jun 21.
11	Hodgkin lymphoma and Epstein-Barr virus (EBV): no evidence to support hit-and-run mechanism in cases classified as non-EBV-associated.Int J Cancer. 2003 May 1;104(5):624-30. doi: 10.1002/ijc.10979.
12	Adenovirus-mediated ribonucleotide reductase R1 gene therapy of human colon adenocarcinoma.Clin Cancer Res. 2003 Oct 1;9(12):4553-61.
13	Childlessness and Health Among Older Adults: Variation Across Five Outcomes and 20 Countries.J Gerontol B Psychol Sci Soc Sci. 2021 Jan 18;76(2):348-359. doi: 10.1093/geronb/gbz153.
14	Imaging retinal inflammatory biomarkers after intravitreal steroid and anti-VEGF treatment in diabetic macular oedema.Acta Ophthalmol. 2017 Aug;95(5):464-471. doi: 10.1111/aos.13294. Epub 2016 Oct 24.
15	Utility of a one-step screening and diagnosis strategy for viremic HCV infection among people who inject drugs in Catalonia.Int J Drug Policy. 2019 Dec;74:236-245. doi: 10.1016/j.drugpo.2019.10.012. Epub 2019 Nov 6.
16	Phase angle as a severity indicator for liver diseases.Nutrition. 2020 Feb;70:110607. doi: 10.1016/j.nut.2019.110607. Epub 2019 Oct 11.
17	Circulating miR-21, miR-210 and miR-146a as potential biomarkers to differentiate acute tubular necrosis from hepatorenal syndrome in patients with liver cirrhosis: a pilot study.Clin Chem Lab Med. 2018 Apr 25;56(5):739-747. doi: 10.1515/cclm-2017-0483.
18	Myositis induced by naked DNA immunization with the gene for histidyl-tRNA synthetase.Hum Gene Ther. 1997 Aug 10;8(12):1469-80. doi: 10.1089/hum.1997.8.12-1469.
19	Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy.Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):E3050-7. doi: 10.1073/pnas.1508057112. Epub 2015 May 26.
20	Attenuation of metabolic syndrome in the ob/ob mouse model by resistant starch intervention is dose dependent.Food Funct. 2019 Dec 11;10(12):7940-7951. doi: 10.1039/c9fo01771b.
21	Angiotensin type 1 receptor expression and interleukin-8 production in polymorphonuclear leukocytes of patients with peripheral arterial disease.J Cardiovasc Pharmacol. 2009 Dec;54(6):520-5. doi: 10.1097/FJC.0b013e3181bfadfd.
22	Functional analysis of the relationship between the neurofibromatosis 2 tumor suppressor and its binding partner, hepatocyte growth factor-regulated tyrosine kinase substrate.Hum Mol Genet. 2002 Dec 1;11(25):3167-78. doi: 10.1093/hmg/11.25.3167.
23	Identification of sample-specific regulations using integrative network level analysis.BMC Cancer. 2015 Apr 28;15:319. doi: 10.1186/s12885-015-1265-2.
24	Time trends in the prevalence of cancer and non-cancer diseases among older U.S. adults: Medicare-based analysis.Exp Gerontol. 2018 Sep;110:267-276. doi: 10.1016/j.exger.2018.06.017. Epub 2018 Jun 19.
25	Search for age-related macular degeneration risk variants in Alzheimer disease genes and pathways.Neurobiol Aging. 2014 Jun;35(6):1510.e7-18. doi: 10.1016/j.neurobiolaging.2013.12.007. Epub 2013 Dec 19.
26	The implications of DSM-III personality disorders for patients with major depression.J Affect Disord. 1984 Dec;7(3-4):309-18. doi: 10.1016/0165-0327(84)90052-1.
27	Survival of patients with structurally-grouped TP53 mutations in ovarian and breast cancers.Oncotarget. 2015 Jul 30;6(21):18641-52. doi: 10.18632/oncotarget.4080.
28	A novel TP53 pathway influences the HGS-mediated exosome formation in colorectal cancer.Sci Rep. 2016 Jun 17;6:28083. doi: 10.1038/srep28083.
29	Does TP53 mutation promote ovarian cancer metastasis to omentum by regulating lipid metabolism?.Med Hypotheses. 2013 Oct;81(4):515-20. doi: 10.1016/j.mehy.2013.06.009. Epub 2013 Jul 20.
30	Factor structure, reliability, and validity of the Japanese version of the Hoarding Rating Scale-Self-Report (HRS-SR-J).Neuropsychiatr Dis Treat. 2017 May 9;13:1235-1243. doi: 10.2147/NDT.S133471. eCollection 2017.
31	Hrs controls sorting of the epithelial Na+ channel between endosomal degradation and recycling pathways.J Biol Chem. 2010 Oct 1;285(40):30523-30. doi: 10.1074/jbc.M110.150755. Epub 2010 Jul 30.
32	Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking.J Mol Biol. 2008 Oct 10;382(3):638-51. doi: 10.1016/j.jmb.2008.07.045. Epub 2008 Jul 25.
33	UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors.Cancer. 2013 Feb 15;119(4):915-23. doi: 10.1002/cncr.27785. Epub 2012 Sep 18.
34	Neurofibromatosis 2 (NF2) tumor suppressor schwannomin and its interacting protein HRS regulate STAT signaling.Hum Mol Genet. 2002 Dec 1;11(25):3179-89. doi: 10.1093/hmg/11.25.3179.
35	Epigenetic meta-analysis across three civilian cohorts identifies NRG1 and HGS as blood-based biomarkers for post-traumatic stress disorder.Epigenomics. 2018 Dec;10(12):1585-1601. doi: 10.2217/epi-2018-0049. Epub 2018 Nov 20.
36	Investigation of coordination and order in transcription regulation of innate and adaptive immunity genes in type 1 diabetes.BMC Med Genomics. 2017 Jan 31;10(1):7. doi: 10.1186/s12920-017-0243-8.
37	Hydrogen-rich saline prevents bone loss in diabetic rats induced by streptozotocin.Int Orthop. 2017 Oct;41(10):2119-2128. doi: 10.1007/s00264-017-3581-4. Epub 2017 Jul 26.
38	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.
39	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.
40	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.
41	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
42	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
43	Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
44	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
45	Calcineurin is an important factor involved in glucose uptake in human adipocytes. Mol Cell Biochem. 2018 Aug;445(1-2):157-168. doi: 10.1007/s11010-017-3261-0. Epub 2018 Jan 27.
46	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.
47	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
48	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.
49	Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.