Details of Drug Off-Target (DOT)

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

• DOT Name: Transferrin receptor protein 2 (TFR2)
• Synonyms: TfR2
• Gene Name: TFR2
• Related Disease:
  Aplastic anemia
  Hemochromatosis type 3
  Hereditary hemochromatosis
  Liver cirrhosis
  Acute erythroid leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Age-related macular degeneration
  Astrocytoma
  Beta thalassemia
  Cardiac failure
  Cardiovascular disease
  Childhood myelodysplastic syndrome
  Congestive heart failure
  Coronary atherosclerosis
  Coronary heart disease
  Hemochromatosis
  Hemochromatosis type 4
  Hemoglobin H disease
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Myelodysplastic syndrome
  Neoplasm
  Parkinson disease
  Small lymphocytic lymphoma
  Glycogen storage disease type II
  Hemochromatosis type 2
  Hepatitis C virus infection
  Porphyria cutanea tarda
  Acute leukaemia
  Acute lymphocytic leukaemia
  Beta-thalassemia intermedia
  Beta-thalassemia major
  Childhood acute lymphoblastic leukemia
  IRIDA syndrome
  Iron-deficiency anemia
• UniProt ID: TFR2_HUMAN
• Pfam ID: PF02225 ; PF04389
• Sequence:
  MERLWGLFQRAQQLSPRSSQTVYQRVEGPRKGHLEEEEEDGEEGAETLAHFCPMELRGPE
  PLGSRPRQPNLIPWAAAGRRAAPYLVLTALLIFTGAFLLGYVAFRGSCQACGDSVLVVSE
  DVNYEPDLDFHQGRLYWSDLQAMFLQFLGEGRLEDTIRQTSLRERVAGSAGMAALTQDIR
  AALSRQKLDHVWTDTHYVGLQFPDPAHPNTLHWVDEAGKVGEQLPLEDPDVYCPYSAIGN
  VTGELVYAHYGRPEDLQDLRARGVDPVGRLLLVRVGVISFAQKVTNAQDFGAQGVLIYPE
  PADFSQDPPKPSLSSQQAVYGHVHLGTGDPYTPGFPSFNQTQFPPVASSGLPSIPAQPIS
  ADIASRLLRKLKGPVAPQEWQGSLLGSPYHLGPGPRLRLVVNNHRTSTPINNIFGCIEGR
  SEPDHYVVIGAQRDAWGPGAAKSAVGTAILLELVRTFSSMVSNGFRPRRSLLFISWDGGD
  FGSVGSTEWLEGYLSVLHLKAVVYVSLDNAVLGDDKFHAKTSPLLTSLIESVLKQVDSPN
  HSGQTLYEQVVFTNPSWDAEVIRPLPMDSSAYSFTAFVGVPAVEFSFMEDDQAYPFLHTK
  EDTYENLHKVLQGRLPAVAQAVAQLAGQLLIRLSHDRLLPLDFGRYGDVVLRHIGNLNEF
  SGDLKARGLTLQWVYSARGDYIRAAEKLRQEIYSSEERDERLTRMYNVRIMRVEFYFLSQ
  YVSPADSPFRHIFMGRGDHTLGALLDHLRLLRSNSSGTPGATSSTGFQESRFRRQLALLT
  WTLQGAANALSGDVWNIDNNF
• Function: Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner. May be involved in iron metabolism, hepatocyte function and erythrocyte differentiation.
• Tissue Specificity: Predominantly expressed in liver. While the alpha form is also expressed in spleen, lung, muscle, prostate and peripheral blood mononuclear cells, the beta form is expressed in all tissues tested, albeit weakly.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway: Transferrin endocytosis and recycling (R-HSA-917977)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aplastic anemia	DISJRSC0	Definitive	Altered Expression	[1]
Hemochromatosis type 3	DIS64BFY	Definitive	Autosomal recessive	[2]
Hereditary hemochromatosis	DISVG5MT	Definitive	Genetic Variation	[3]
Liver cirrhosis	DIS4G1GX	Definitive	Genetic Variation	[4]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[5]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[7]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[8]
Astrocytoma	DISL3V18	Strong	Biomarker	[9]
Beta thalassemia	DIS5RCQK	Strong	Biomarker	[10]
Cardiac failure	DISDC067	Strong	Genetic Variation	[11]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[12]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Altered Expression	[5]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[11]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[12]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[12]
Hemochromatosis	DISAPY0H	Strong	Genetic Variation	[13]
Hemochromatosis type 4	DIS7240J	Strong	Genetic Variation	[14]
Hemoglobin H disease	DISHFWO5	Strong	Genetic Variation	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[16]
leukaemia	DISS7D1V	Strong	Altered Expression	[5]
Leukemia	DISNAKFL	Strong	Altered Expression	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[16]
Parkinson disease	DISQVHKL	Strong	Biomarker	[17]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[18]
Glycogen storage disease type II	DISXZPBC	moderate	Posttranslational Modification	[8]
Hemochromatosis type 2	DISYM9UP	moderate	Biomarker	[19]
Hepatitis C virus infection	DISQ0M8R	moderate	Genetic Variation	[20]
Porphyria cutanea tarda	DISHNFD7	moderate	Genetic Variation	[20]
Acute leukaemia	DISDQFDI	Limited	Genetic Variation	[6]
Acute lymphocytic leukaemia	DISPX75S	Limited	Genetic Variation	[6]
Beta-thalassemia intermedia	DISYQ0NL	Limited	Genetic Variation	[21]
Beta-thalassemia major	DISW06BV	Limited	Biomarker	[10]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Genetic Variation	[6]
IRIDA syndrome	DISPN8YW	Limited	Genetic Variation	[21]
Iron-deficiency anemia	DIS0VQYF	Limited	Genetic Variation	[22]

8 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 Transferrin receptor protein 2 (TFR2).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transferrin receptor protein 2 (TFR2).	[24]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Transferrin receptor protein 2 (TFR2).	[26]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Transferrin receptor protein 2 (TFR2).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transferrin receptor protein 2 (TFR2).	[29]
KENPAULLONE	DMAGVXW	Patented	KENPAULLONE decreases the expression of Transferrin receptor protein 2 (TFR2).	[30]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of Transferrin receptor protein 2 (TFR2).	[30]
SU9516	DMQHG0R	Investigative	SU9516 decreases the expression of Transferrin receptor protein 2 (TFR2).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Transferrin receptor protein 2 (TFR2).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transferrin receptor protein 2 (TFR2).	[28]

References

• [1] A composite mouse model of aplastic anemia complicated with iron overload.Exp Ther Med. 2018 Feb;15(2):1449-1455. doi: 10.3892/etm.2017.5523. Epub 2017 Nov 17.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Transferrin Receptors TfR1 and TfR2 Bind Transferrin through Differing Mechanisms.Biochemistry. 2018 Mar 6;57(9):1552-1559. doi: 10.1021/acs.biochem.8b00006. Epub 2018 Feb 12.
• [4] Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis.Hum Mol Genet. 2014 Jul 15;23(14):3883-90. doi: 10.1093/hmg/ddu076. Epub 2014 Feb 20.
• [5] Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells.Blood. 2001 Nov 1;98(9):2714-9. doi: 10.1182/blood.v98.9.2714.
• [6] Analysis of HFE and TFR2 gene mutations in patients with acute leukemia.Leuk Res. 2005 Jun;29(6):661-4. doi: 10.1016/j.leukres.2005.01.001. Epub 2005 Feb 12.
• [7] Transferrin receptor 2 is frequently expressed in human cancer cell lines.Blood Cells Mol Dis. 2007 Jul-Aug;39(1):82-91. doi: 10.1016/j.bcmd.2007.02.003. Epub 2007 Apr 10.
• [8] Variability of the transferrin receptor 2 gene in AMD.Dis Markers. 2014;2014:507356. doi: 10.1155/2014/507356. Epub 2014 Feb 6.
• [9] Expression of iron-related genes in human brain and brain tumors.BMC Neurosci. 2009 Apr 22;10:36. doi: 10.1186/1471-2202-10-36.
• [10] mRNA expression of iron regulatory genes in beta-thalassemia intermedia and beta-thalassemia major mouse models.Am J Hematol. 2006 Jul;81(7):479-83. doi: 10.1002/ajh.20549.
• [11] Diferric transferrin regulates transferrin receptor 2 protein stability.Blood. 2004 Dec 15;104(13):4287-93. doi: 10.1182/blood-2004-06-2477. Epub 2004 Aug 19.
• [12] Association between genetic variations in TFR2 gene and coronary heart disease in Chinese: a case-control study.J Cardiovasc Med (Hagerstown). 2014 May;15(5):397-401. doi: 10.2459/JCM.0b013e32836206f3.
• [13] Identification of novel mutations in HFE, HFE2, TfR2, and SLC40A1 genes in Chinese patients affected by hereditary hemochromatosis.Int J Hematol. 2017 Apr;105(4):521-525. doi: 10.1007/s12185-016-2150-8. Epub 2016 Nov 28.
• [14] Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE).Hematol Oncol Clin North Am. 2014 Aug;28(4):625-35, v. doi: 10.1016/j.hoc.2014.04.006. Epub 2014 Jun 2.
• [15] Can defects in transferrin receptor 2 and hereditary hemochromatosis genes account for iron overload in HbH disease?.Blood Cells Mol Dis. 2003 Jan-Feb;30(1):107-11. doi: 10.1016/s1079-9796(03)00013-5.
• [16] Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma.Histopathology. 2019 Jul;75(1):63-73. doi: 10.1111/his.13847. Epub 2019 May 16.
• [17] Pooled analysis of iron-related genes in Parkinson's disease: association with transferrin.Neurobiol Dis. 2014 Feb;62:172-8. doi: 10.1016/j.nbd.2013.09.019. Epub 2013 Oct 8.
• [18] Predominantly post-transcriptional regulation of activation molecules in chronic lymphocytic leukemia: the case of transferrin receptors.Blood Cells Mol Dis. 2008 Sep-Oct;41(2):203-9. doi: 10.1016/j.bcmd.2008.05.003. Epub 2008 Jul 14.
• [19] Current approaches to the management of hemochromatosis.Hematology Am Soc Hematol Educ Program. 2006:36-41. doi: 10.1182/asheducation-2006.1.36.
• [20] High prevalence of HFE gene mutations in patients with porphyria cutanea tarda in the Czech Republic.Br J Dermatol. 2008 Sep;159(3):585-90. doi: 10.1111/j.1365-2133.2008.08693.x. Epub 2008 Jun 28.
• [21] A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis.Haematologica. 2015 Feb;100(2):167-77. doi: 10.3324/haematol.2014.116723. Epub 2014 Nov 25.
• [22] TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia.Hum Mol Genet. 2012 May 1;21(9):2124-31. doi: 10.1093/hmg/dds028. Epub 2012 Feb 8.
• [23] 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.
• [24] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [25] Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood. Toxicol Appl Pharmacol. 2017 Apr 15;321:57-66. doi: 10.1016/j.taap.2017.02.019. Epub 2017 Feb 24.
• [26] 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.
• [27] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [28] 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.
• [29] 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.
• [30] A HAMP promoter bioassay system for identifying chemical compounds that modulate hepcidin expression. Exp Hematol. 2015 May;43(5):404-413.e5. doi: 10.1016/j.exphem.2015.01.005. Epub 2015 Jan 26.