Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZEN192)

DOT Name Thrombopoietin receptor (MPL)
Synonyms TPO-R; Myeloproliferative leukemia protein; Proto-oncogene c-Mpl; CD antigen CD110
Gene Name MPL
Related Disease
Congenital amegakaryocytic thrombocytopenia 1 ( )
Obsolete congenital amegakaryocytic thrombocytopenia ( )
Thrombocythemia 2 ( )
Obsolete hereditary isolated aplastic anemia ( )
Thrombocythemia ( )
UniProt ID
TPOR_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
8G04
Pfam ID
PF09067
Sequence
MPSWALFMVTSCLLLAPQNLAQVSSQDVSLLASDSEPLKCFSRTFEDLTCFWDEEEAAPS
GTYQLLYAYPREKPRACPLSSQSMPHFGTRYVCQFPDQEEVRLFFPLHLWVKNVFLNQTR
TQRVLFVDSVGLPAPPSIIKAMGGSQPGELQISWEEPAPEISDFLRYELRYGPRDPKNST
GPTVIQLIATETCCPALQRPHSASALDQSPCAQPTMPWQDGPKQTSPSREASALTAEGGS
CLISGLQPGNSYWLQLRSEPDGISLGGSWGSWSLPVTVDLPGDAVALGLQCFTLDLKNVT
CQWQQQDHASSQGFFYHSRARCCPRDRYPIWENCEEEEKTNPGLQTPQFSRCHFKSRNDS
IIHILVEVTTAPGTVHSYLGSPFWIHQAVRLPTPNLHWREISSGHLELEWQHPSSWAAQE
TCYQLRYTGEGHQDWKVLEPPLGARGGTLELRPRSRYRLQLRARLNGPTYQGPWSSWSDP
TRVETATETAWISLVTALHLVLGLSAVLGLLLLRWQFPAHYRRLRHALWPSLPDLHRVLG
QYLRDTAALSPPKATVSDTCEEVEPSLLEILPKSSERTPLPLCSSQAQMDYRRLQPSCLG
TMPLSVCPPMAESGSCCTTHIANHSYLPLSYWQQP
Function Receptor for thrombopoietin that acts as a primary regulator of megakaryopoiesis and platelet production. May represent a regulatory molecule specific for TPO-R-dependent immune responses.
Tissue Specificity Expressed at a low level in a large number of cells of hematopoietic origin. Isoform 1 and isoform 2 are always found to be coexpressed.
KEGG Pathway
Cytokine-cytokine receptor interaction (hsa04060 )
JAK-STAT sig.ling pathway (hsa04630 )
Reactome Pathway
Platelet Aggregation (Plug Formation) (R-HSA-76009 )

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Congenital amegakaryocytic thrombocytopenia 1 DISSBM2M Definitive Autosomal recessive [1]
Obsolete congenital amegakaryocytic thrombocytopenia DISTJQ17 Definitive Autosomal recessive [2]
Thrombocythemia 2 DISTRTMY Definitive Autosomal dominant [1]
Obsolete hereditary isolated aplastic anemia DIS2B0NW Supportive Autosomal dominant [3]
Thrombocythemia DISL38J3 Supportive Autosomal dominant [4]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
4 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic trioxide DM61TA4 Approved Arsenic trioxide decreases the expression of Thrombopoietin receptor (MPL). [5]
Midostaurin DMI6E0R Approved Midostaurin increases the expression of Thrombopoietin receptor (MPL). [7]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of Thrombopoietin receptor (MPL). [8]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Thrombopoietin receptor (MPL). [10]
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2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Hydroquinone DM6AVR4 Approved Hydroquinone decreases the methylation of Thrombopoietin receptor (MPL). [6]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Thrombopoietin receptor (MPL). [9]
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References

1 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
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 Exome sequencing identifies MPL as a causative gene in familial aplastic anemia. Haematologica. 2012 Apr;97(4):524-8. doi: 10.3324/haematol.2011.052787. Epub 2011 Dec 16.
4 Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
5 Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
6 Hypomethylation mediated by decreased DNMTs involves in the activation of proto-oncogene MPL in TK6 cells treated with hydroquinone. Toxicol Lett. 2012 Mar 25;209(3):239-45. doi: 10.1016/j.toxlet.2011.12.020. Epub 2012 Jan 8.
7 Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells. Toxicol In Vitro. 2009 Sep;23(6):979-85. doi: 10.1016/j.tiv.2009.06.027. Epub 2009 Jun 30.
8 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
9 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.
10 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.