Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4ALHBQ)

• DOT Name: SH2B adapter protein 3 (SH2B3)
• Synonyms: Lymphocyte adapter protein; Lymphocyte-specific adapter protein Lnk; Signal transduction protein Lnk
• Gene Name: SH2B3
• Related Disease:
  Growth retardation-mild developmental delay-chronic hepatitis syndrome
  Primary familial polycythemia due to EPO receptor mutation
  Schizophrenia
  Thrombocythemia 1
• UniProt ID: SH2B3_HUMAN
• Pfam ID: PF08916 ; PF00017
• Sequence:
  MNGPALQPSSPSSAPSASPAAAPRGWSEFCELHAVAAARELARQYWLFAREHPQHAPLRA
  ELVSLQFTDLFQRYFCREVRDGRAPGRDYRDTGRGPPAKAEASPEPGPGPAAPGLPKARS
  SEELAPPRPPGPCSFQHFRRSLRHIFRRRSAGELPAAHTAAAPGTPGEAAETPARPGLAK
  KFLPWSLAREPPPEALKEAVLRYSLADEASMDSGARWQRGRLALRRAPGPDGPDRVLELF
  DPPKSSRPKLQAACSSIQEVRWCTRLEMPDNLYTFVLKVKDRTDIIFEVGDEQQLNSWMA
  ELSECTGRGLESTEAEMHIPSALEPSTSSSPRGSTDSLNQGASPGGLLDPACQKTDHFLS
  CYPWFHGPISRVKAAQLVQLQGPDAHGVFLVRQSETRRGEYVLTFNFQGIAKHLRLSLTE
  RGQCRVQHLHFPSVVDMLHHFQRSPIPLECGAACDVRLSSYVVVVSQPPGSCNTVLFPFS
  LPHWDSESLPHWGSELGLPHLSSSGCPRGLSPEGLPGRSSPPEQIFHLVPSPEELANSLQ
  HLEHEPVNRARDSDYEMDSSSRSHLRAIDNQYTPL
• Function: Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
• Tissue Specificity: Preferentially expressed by lymphoid cell lines.
• KEGG Pathway: Neurotrophin sig.ling pathway (hsa04722)
• Reactome Pathway:
  Negative regulation of FLT3 (R-HSA-9706369)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Regulation of KIT signaling (R-HSA-1433559)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Growth retardation-mild developmental delay-chronic hepatitis syndrome	DISB0J5I	Supportive	Autosomal recessive	[1]
Primary familial polycythemia due to EPO receptor mutation	DISFVI97	No Known	Unknown	[2]
Schizophrenia	DISSRV2N	No Known	Unknown	[3]
Thrombocythemia 1	DISVREYO	No Known	Unknown	[4]

2 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 SH2B adapter protein 3 (SH2B3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of SH2B adapter protein 3 (SH2B3).	[19]

15 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 SH2B adapter protein 3 (SH2B3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of SH2B adapter protein 3 (SH2B3).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SH2B adapter protein 3 (SH2B3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SH2B adapter protein 3 (SH2B3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of SH2B adapter protein 3 (SH2B3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of SH2B adapter protein 3 (SH2B3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SH2B adapter protein 3 (SH2B3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of SH2B adapter protein 3 (SH2B3).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of SH2B adapter protein 3 (SH2B3).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of SH2B adapter protein 3 (SH2B3).	[15]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of SH2B adapter protein 3 (SH2B3).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of SH2B adapter protein 3 (SH2B3).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of SH2B adapter protein 3 (SH2B3).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of SH2B adapter protein 3 (SH2B3).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of SH2B adapter protein 3 (SH2B3).	[21]

References

• [1] Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood. 2013 Oct 3;122(14):2425-32. doi: 10.1182/blood-2013-05-500850. Epub 2013 Aug 1.
• [2] Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. Haematologica. 2016 Nov;101(11):1306-1318. doi: 10.3324/haematol.2016.144063. Epub 2016 Sep 20.
• [3] Increased co-expression of genes harboring the damaging de novo mutations in Chinese schizophrenic patients during prenatal development. Sci Rep. 2015 Dec 15;5:18209. doi: 10.1038/srep18209.
• [4] Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat Genet. 2014 Jun;46(6):629-34. doi: 10.1038/ng.2962. Epub 2014 Apr 28.
• [5] 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.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.