Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQSKW7U)

• DOT Name: SH2 domain-containing protein 2A (SH2D2A)
• Synonyms: SH2 domain-containing adapter protein; T cell-specific adapter protein; TSAd; VEGF receptor-associated protein
• Gene Name: SH2D2A
• Related Disease:
  Chronic inflammatory demyelinating polyneuropathy
  Multiple sclerosis
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Hypothyroidism
  Juvenile idiopathic arthritis
  STAT3-related early-onset multisystem autoimmune disease
• UniProt ID: SH22A_HUMAN
• Pfam ID: PF00017
• Sequence:
  MEFPLAQICPQGSHEAPIPTFSTFQITDMTRRSCQNLGYTAASPQAPEAASNTGNAERAE
  EVPGEGSLFLQAETRAWFQKTQAHWLLQHGAAPAWFHGFITRREAERLLEPKPQGCYLVR
  FSESAVTFVLTYRSRTCCRHFLLAQLRDGRHVVLGEDSAHARLQDLLLHYTAHPLSPYGE
  TLTEPLARQTPEPAGLSLRTEESNFGSKSQDPNPQYSPIIKQGQAPVPMQKEGAGEKEPS
  QLLRPKPPIPAKPQLPPEVYTIPVPRHRPAPRPKPSNPIYNEPDEPIAFYAMGRGSPGEA
  PSNIYVEVEDEGLPATLGHPVLRKSWSRPVPGGQNTGGSQLHSENSVIGQGPPLPHQPPP
  AWRHTLPHNLSRQVLQDRGQAWLPLGPPQ
• Function: Could be a T-cell-specific adapter protein involved in the control of T-cell activation. May play a role in the CD4-p56-LCK-dependent signal transduction pathway. Could also play an important role in normal and pathological angiogenesis. Could be an adapter protein that facilitates and regulates interaction of KDR with effector proteins important to endothelial cell survival and proliferation.
• Tissue Specificity: Expression limited to tissues of the immune system and, in particular, activated T-cells. Expressed in peripheral blood leukocytes, thymus and spleen. Much lower expression or undetectable, in brain, placenta, skeletal muscle, prostate, testis, ovary, small intestine, and colon. Expressed at low levels in unstimulated T-cells, but not expressed in normal resting or activated B-cells. According to PubMed:10692392, expression is not restricted to activated T-cells, but strongly expressed in blood cell lineages, the endothelium and other cell and tissue types, such as heart, lung, and liver.
• KEGG Pathway: VEGF sig.ling pathway (hsa04370)
• Reactome Pathway: VEGFA-VEGFR2 Pathway (R-HSA-4420097)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic inflammatory demyelinating polyneuropathy	DISNGBLD	Definitive	Genetic Variation	[1]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[2]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[3]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[2]

9 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 SH2 domain-containing protein 2A (SH2D2A).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of SH2 domain-containing protein 2A (SH2D2A).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SH2 domain-containing protein 2A (SH2D2A).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of SH2 domain-containing protein 2A (SH2D2A).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of SH2 domain-containing protein 2A (SH2D2A).	[8]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of SH2 domain-containing protein 2A (SH2D2A).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH2 domain-containing protein 2A (SH2D2A).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of SH2 domain-containing protein 2A (SH2D2A).	[11]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of SH2 domain-containing protein 2A (SH2D2A).	[12]

References

• [1] Susceptibility to chronic inflammatory demyelinating polyradiculoneuropathy is associated to polymorphic GA repeat in the SH2D2A gene.J Neuroimmunol. 2008 Jul 15;197(2):124-7. doi: 10.1016/j.jneuroim.2008.04.003. Epub 2008 Jun 3.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene.Genes Immun. 2004 Jun;5(4):310-2. doi: 10.1038/sj.gene.6364093.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [10] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [11] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [12] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.