Details of Drug Off-Target (DOT)

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

• DOT Name: Megakaryocyte and platelet inhibitory receptor G6b (MPIG6B)
• Synonyms: Protein G6b
• Gene Name: MPIG6B
• Related Disease:
  Classic Hodgkin lymphoma
  Thrombocytopenia, anemia, and myelofibrosis
  Autoimmune disease
  B-cell lymphoma
  Hepatitis C virus infection
  Inherited bleeding disorder, platelet-type
  Malignant soft tissue neoplasm
  Pancytopenia
  Primary myelofibrosis
  Sarcoma
  Systemic lupus erythematosus
  Type-1 diabetes
  Ulcerative colitis
  Myelofibrosis
  Anemia
  Neoplasm
  Rheumatoid arthritis
  Sickle-cell anaemia
  Stroke
  Thrombocytopenia
• UniProt ID: G6B_HUMAN
• PDB ID: 6R0X
• Pfam ID: PF15096
• Sequence:
  MAVFLQLLPLLLSRAQGNPGASLDGRPGDRVNLSCGGVSHPIRWVWAPSFPACKGLSKGR
  RPILWASSSGTPTVPPLQPFVGRLRSLDSGIRRLELLLSAGDSGTFFCKGRHEDESRTVL
  HVLGDRTYCKAPGPTHGSVYPQLLIPLLGAGLVLGLGALGLVWWLHRRLPPQPIRPLPRF
  APLVKTEPQRPVKEEEPKIPGDLDQEPSLLYADLDHLALSRPRRLSTADPADASTIYAVV
  V
• Function: Inhibitory receptor that acts as a critical regulator of hematopoietic lineage differentiation, megakaryocyte function and platelet production. Inhibits platelet aggregation and activation by agonists such as ADP and collagen-related peptide. This regulation of megakaryocate function as well as platelet production ann activation is done through the inhibition (via the 2 ITIM motifs) of the receptors CLEC1B and GP6:FcRgamma signaling. Appears to operate in a calcium-independent manner ; Isoform B, displayed in this entry, is the only isoform to contain both a transmembrane region and 2 immunoreceptor tyrosine-based inhibitor motifs (ITIMs) and, thus, the only one which probably has a role of inhibitory receptor. Isoform A may be the activating counterpart of isoform B.
• Tissue Specificity: Expressed in platelets. Expressed in a restricted set of hematopoietic cell lines including the erythroleukemia cell line K-562 and the T-cell leukemia cell lines MOLT-4 and Jurkat. Not detected in the monocyte-like cell line U-937, the B-cell-like cell line Raji, the fibroblast cell lines TK and HeLa, or the natural killer cell lines NKL, NK 62 and YT.
• Reactome Pathway: GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Genetic Variation	[1]
Thrombocytopenia, anemia, and myelofibrosis	DISAVEMK	Definitive	Autosomal recessive	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[5]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Biomarker	[6]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[7]
Pancytopenia	DISVKEHV	Strong	Genetic Variation	[8]
Primary myelofibrosis	DIS6L0CN	Strong	Genetic Variation	[9]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[7]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[10]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[11]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[12]
Myelofibrosis	DISIMP21	moderate	Genetic Variation	[9]
Anemia	DISTVL0C	Limited	Genetic Variation	[13]
Neoplasm	DISZKGEW	Limited	Biomarker	[14]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[15]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[16]
Stroke	DISX6UHX	Limited	Genetic Variation	[16]
Thrombocytopenia	DISU61YW	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Megakaryocyte and platelet inhibitory receptor G6b (MPIG6B) affects the response to substance of Fluorouracil.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Megakaryocyte and platelet inhibitory receptor G6b (MPIG6B).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Megakaryocyte and platelet inhibitory receptor G6b (MPIG6B).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Megakaryocyte and platelet inhibitory receptor G6b (MPIG6B).	[19]

References

• [1] Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin's lymphoma.Nat Commun. 2013;4:2549. doi: 10.1038/ncomms3549.
• [2] 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.
• [3] A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population.Nat Genet. 2009 Dec;41(12):1325-9. doi: 10.1038/ng.482. Epub 2009 Nov 15.
• [4] Diffuse large B-cell lymphoma and its variants.Croat Med J. 2002 Oct;43(5):535-40.
• [5] Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia.Blood. 2000 Nov 15;96(10):3578-84.
• [6] Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function.Sci Signal. 2012 Oct 30;5(248):ra78. doi: 10.1126/scisignal.2002936.
• [7] High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas.Am J Surg Pathol. 2009 Jun;33(6):863-73. doi: 10.1097/PAS.0b013e31819287b8.
• [8] Case report of a novel MPIG6B gene mutation in a Chinese boy with pancytopenia and splenomegaly.Gene. 2019 Oct 5;715:143957. doi: 10.1016/j.gene.2019.143957. Epub 2019 Jul 2.
• [9] Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis.Blood. 2018 Sep 27;132(13):1413-1425. doi: 10.1182/blood-2017-10-802975. Epub 2018 Jun 11.
• [10] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [11] Interactions between maternal killer cell immunoglobulin receptor genes and foetal HLA ligand genes contribute to type 1 diabetes susceptibility in Han Chinese.Int J Immunogenet. 2016 Jun;43(3):125-30. doi: 10.1111/iji.12257. Epub 2016 Mar 17.
• [12] Genome-wide association identifies multiple ulcerative colitis susceptibility loci.Nat Genet. 2010 Apr;42(4):332-7. doi: 10.1038/ng.549. Epub 2010 Mar 14.
• [13] Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia.Eur J Haematol. 2017 Mar;98(3):218-227. doi: 10.1111/ejh.12819. Epub 2017 Jan 3.
• [14] Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study.Lancet Oncol. 2015 May;16(5):541-9. doi: 10.1016/S1470-2045(15)70106-3. Epub 2015 Apr 1.
• [15] A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis.Ann Rheum Dis. 2011 Feb;70(2):259-65. doi: 10.1136/ard.2009.126821. Epub 2010 Dec 14.
• [16] Patterns of low-affinity immunoglobulin receptor polymorphisms in stroke and homozygous sickle cell disease.Am J Hematol. 2002 Feb;69(2):109-14. doi: 10.1002/ajh.10048.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [19] 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.
• [20] 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.