Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLU49I5)

DOT Name	SH2 domain-containing protein 1A (SH2D1A)
Synonyms	Duncan disease SH2-protein; Signaling lymphocytic activation molecule-associated protein; SLAM-associated protein; T-cell signal transduction molecule SAP
Gene Name	SH2D1A
Related Disease	Aplastic anemia ( ) Chronic obstructive pulmonary disease ( ) Epstein barr virus infection ( ) Hemophagocytic syndrome ( ) Metabolic disorder ( ) Non-insulin dependent diabetes ( ) Type-1 diabetes ( ) Acute coronary syndrome ( ) Acute megakaryoblastic leukemia ( ) Acute myocardial infarction ( ) Advanced cancer ( ) Amyloidosis ( ) Autism spectrum disorder ( ) Autoimmune disease ( ) B-cell lymphoma ( ) B-cell neoplasm ( ) Breast cancer ( ) Burkitt lymphoma ( ) Classic Hodgkin lymphoma ( ) Common variable immunodeficiency ( ) Endometriosis ( ) Graves disease ( ) Hepatitis B virus infection ( ) Hepatitis C virus infection ( ) Immune system disorder ( ) Immunodeficiency ( ) Inflammatory bowel disease ( ) Influenza ( ) Leukemia ( ) Lupus ( ) Lymphoproliferative syndrome ( ) Neoplasm ( ) Pulmonary disease ( ) Rheumatoid arthritis ( ) Systemic lupus erythematosus ( ) Tuberculosis ( ) Vulvovaginal Candidiasis ( ) X-linked lymphoproliferative disease due to SH2D1A deficiency ( ) XIAP deficiency ( ) Hantavirus infection ( ) Oral candidiasis ( ) Pneumonia ( ) Amyotrophic lateral sclerosis ( ) Breast carcinoma ( ) Cardiomyopathy ( ) Nervous system disease ( ) T-cell leukaemia ( ) Vasculitis ( )
UniProt ID	SH21A_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1D1Z; 1D4T; 1D4W; 1KA6; 1KA7; 1M27
Pfam ID	PF00017
Sequence	MDAVAVYHGKISRETGEKLLLATGLDGSYLLRDSESVPGVYCLCVLYHGYIYTYRVSQTE TGSWSAETAPGVHKRYFRKIKNLISAFQKPDQGIVIPLQYPVEKKSSARSTQGTTGIRED PDVCLKAP
Function	Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7. In SLAM signaling seems to cooperate with SH2D1B/EAT-2. Initially it has been proposed that association with SLAMF1 prevents SLAMF1 binding to inhibitory effectors including INPP5D/SHIP1 and PTPN11/SHP-2. However, by simultaneous interactions, recruits FYN which subsequently phosphorylates and activates SLAMF1. Positively regulates CD244/2B4- and CD84-mediated natural killer (NK) cell functions. Can also promote CD48-, SLAMF6 -, LY9-, and SLAMF7-mediated NK cell activation. In the context of NK cell-mediated cytotoxicity enhances conjugate formation with target cells. May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3.
Tissue Specificity	Expressed at a high level in thymus and lung, with a lower level of expression in spleen and liver. Expressed in peripheral blood leukocytes, including T-lymphocytes. Tends to be expressed at lower levels in peripheral blood leukocytes in patients with rheumatoid arthritis.
KEGG Pathway	.tural killer cell mediated cytotoxicity (hsa04650 )
Reactome Pathway	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933 )

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Aplastic anemia	DISJRSC0	Definitive	Genetic Variation	[1]
Chronic obstructive pulmonary disease	DISQCIRF	Definitive	Biomarker	[2]
Epstein barr virus infection	DISOO0WT	Definitive	Genetic Variation	[3]
Hemophagocytic syndrome	DIS3TMN4	Definitive	Altered Expression	[4]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[6]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[6]
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[7]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Biomarker	[8]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[10]
Amyloidosis	DISHTAI2	Strong	Biomarker	[11]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[12]
Autoimmune disease	DISORMTM	Strong	Biomarker	[13]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[14]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[15]
Breast cancer	DIS7DPX1	Strong	Biomarker	[16]
Burkitt lymphoma	DIS9D5XU	Strong	Genetic Variation	[17]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[18]
Common variable immunodeficiency	DISHE7JQ	Strong	Altered Expression	[19]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[20]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[21]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[22]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[23]
Immune system disorder	DISAEGPH	Strong	Biomarker	[24]
Immunodeficiency	DIS093I0	Strong	Biomarker	[25]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[3]
Influenza	DIS3PNU3	Strong	Biomarker	[26]
Leukemia	DISNAKFL	Strong	Genetic Variation	[27]
Lupus	DISOKJWA	Strong	Altered Expression	[28]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[29]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Pulmonary disease	DIS6060I	Strong	Biomarker	[2]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[30]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[31]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[32]
Vulvovaginal Candidiasis	DISRCR6D	Strong	Altered Expression	[33]
X-linked lymphoproliferative disease due to SH2D1A deficiency	DISAMB1P	Strong	X-linked	[34]
XIAP deficiency	DIS24CGE	Strong	Biomarker	[3]
Hantavirus infection	DISZFTMH	moderate	Biomarker	[4]
Oral candidiasis	DISAVKAH	moderate	Biomarker	[35]
Pneumonia	DIS8EF3M	moderate	Biomarker	[36]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[37]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[16]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[38]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[39]
T-cell leukaemia	DISJ6YIF	Limited	Biomarker	[40]
Vasculitis	DISQRKDX	Limited	Genetic Variation	[17]
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⏷ Show the Full List of 48 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of SH2 domain-containing protein 1A (SH2D1A).	[41]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of SH2 domain-containing protein 1A (SH2D1A).	[42]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of SH2 domain-containing protein 1A (SH2D1A).	[43]
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1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of SH2 domain-containing protein 1A (SH2D1A).	[44]
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References

1	Frequent mutations in SH2D1A (XLP) in males presenting with high-grade mature B-cell neoplasms.Pediatr Blood Cancer. 2013 Sep;60(9):E85-7. doi: 10.1002/pbc.24525. Epub 2013 Apr 15.
2	Combination of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate for the treatment of inflammatory lung diseases: An in vitro study.Eur J Pharm Sci. 2018 Jul 30;120:96-106. doi: 10.1016/j.ejps.2018.04.042. Epub 2018 Apr 30.
3	X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic.Eur J Pediatr. 2020 Feb;179(2):327-338. doi: 10.1007/s00431-019-03512-7. Epub 2019 Nov 21.
4	Up-regulation of activating transcription factor-5 suppresses SAP expression to activate T cells in hemophagocytic syndrome associated with Epstein-Barr virus infection and immune disorders.Am J Pathol. 2008 Nov;173(5):1397-405. doi: 10.2353/ajpath.2008.080440. Epub 2008 Oct 2.
5	Bone marrow transplant for X-linked protoporphyria with severe hepatic fibrosis.Pediatr Transplant. 2015 Jun;19(4):E106-10. doi: 10.1111/petr.12472. Epub 2015 Apr 9.
6	AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY 2018 POSITION STATEMENT ON INTEGRATION OF INSULIN PUMPS AND CONTINUOUS GLUCOSE MONITORING IN PATIENTS WITH DIABETES MELLITUS.Endocr Pract. 2018 Mar;24(3):302-308. doi: 10.4158/PS-2017-0155.
7	Relationship between quantities of tissue prolapse after percutaneous coronary intervention and neointimal hyperplasia at follow-up on serial optical coherence tomography examination.Int J Cardiol. 2017 Aug 15;241:470-477. doi: 10.1016/j.ijcard.2017.01.155. Epub 2017 Feb 14.
8	Mechanism of irradiation-induced mammary cancer metastasis: A role for SAP-dependent Mkl1 signaling.Mol Oncol. 2015 Oct;9(8):1510-27. doi: 10.1016/j.molonc.2015.04.003. Epub 2015 Apr 30.
9	Changes in fractalkine in patients with ST-elevation myocardial infarction.Coron Artery Dis. 2015 Sep;26(6):516-20. doi: 10.1097/MCA.0000000000000273.
10	SAP domain-dependent Mkl1 signaling stimulates proliferation and cell migration by induction of a distinct gene set indicative of poor prognosis in breast cancer patients.Mol Cancer. 2014 Feb 5;13:22. doi: 10.1186/1476-4598-13-22.
11	Alkaptonuria is a novel human secondary amyloidogenic disease.Biochim Biophys Acta. 2012 Nov;1822(11):1682-91. doi: 10.1016/j.bbadis.2012.07.011. Epub 2012 Jul 28.
12	Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism.J Hum Genet. 2020 Mar;65(3):287-296. doi: 10.1038/s10038-019-0707-0. Epub 2019 Dec 12.
13	Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance.J Allergy Clin Immunol. 2014 Apr;133(4):1149-61. doi: 10.1016/j.jaci.2013.10.051. Epub 2013 Dec 25.
14	Transcript profiling in peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma identifies distinct tumor profile signatures.Mol Cancer Ther. 2005 Dec;4(12):1867-79. doi: 10.1158/1535-7163.MCT-05-0146.
15	Novel Mutations in SH2D1A Gene in X-linked Lymphoproliferative Syndrome, Diagnosed After B-Cell Non-Hodgkin Lymphoma.J Pediatr Hematol Oncol. 2017 May;39(4):e203-e206. doi: 10.1097/MPH.0000000000000815.
16	Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule.Oncotarget. 2017 Jun 6;8(23):37250-37262. doi: 10.18632/oncotarget.16763.
17	Fatal Central Nervous System Lymphocytic Vasculitis after Treatment for Burkitt Lymphoma in a Patient with a SH2D1A Mutation.Pediatr Infect Dis J. 2019 Feb;38(2):e29-e31. doi: 10.1097/INF.0000000000002154.
18	Expression of SH2D1A in five classical Hodgkin's disease-derived cell lines.Int J Cancer. 2003 May 1;104(5):658-61. doi: 10.1002/ijc.10986.
19	Skewed Invariant Natural Killer T (iNKT) Cells, Impaired iNKT:B Cell Help and Decreased SAP Expression in Blood Lymphocytes from Patients with Common Variable Immunodeficiency.Scand J Immunol. 2017 Sep;86(3):171-178. doi: 10.1111/sji.12576.
20	PTPN22/LYP 1858C>T gene polymorphism and susceptibility to endometriosis in a Polish population.J Reprod Immunol. 2009 Jan;79(2):196-200. doi: 10.1016/j.jri.2008.11.004. Epub 2009 Feb 23.
21	General and Specific Genetic Polymorphism of Cytokines-Related Gene in AITD.Mediators Inflamm. 2017;2017:3916395. doi: 10.1155/2017/3916395. Epub 2017 Jan 4.
22	TGF-1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence.PLoS Pathog. 2012;8(3):e1002594. doi: 10.1371/journal.ppat.1002594. Epub 2012 Mar 15.
23	Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells.PLoS Pathog. 2011 May;7(5):e1002045. doi: 10.1371/journal.ppat.1002045. Epub 2011 May 19.
24	X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma.Br J Haematol. 2011 Jan;152(1):13-30. doi: 10.1111/j.1365-2141.2010.08442.x. Epub 2010 Nov 18.
25	2B4-SAP signaling is required for the priming of naive CD8(+) T cells by antigen-expressing B cells and B lymphoma cells.Oncoimmunology. 2016 Dec 27;6(2):e1267094. doi: 10.1080/2162402X.2016.1267094. eCollection 2017.
26	Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP.PLoS Biol. 2011 Nov;9(11):e1001187. doi: 10.1371/journal.pbio.1001187. Epub 2011 Nov 1.
27	Analysis of SH2D1A mutations in patients with severe Epstein-Barr virus infections, Burkitt's lymphoma, and Hodgkin's lymphoma.Ann Hematol. 2002 Aug;81(8):441-7. doi: 10.1007/s00277-002-0490-3. Epub 2002 Jul 20.
28	Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production.J Immunol. 2016 Jun 15;196(12):4915-24. doi: 10.4049/jimmunol.1501523. Epub 2016 May 11.
29	Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency.J Clin Invest. 2009 Oct;119(10):2976-89. doi: 10.1172/JCI39518. Epub 2009 Sep 14.
30	The functional PTPN22 C1858T polymorphism confers risk for rheumatoid arthritis in patients from Central Mexico.Clin Rheumatol. 2016 Jun;35(6):1457-62. doi: 10.1007/s10067-016-3223-z. Epub 2016 Mar 7.
31	Signaling lymphocyte activation molecule family in systemic lupus erythematosus.Clin Immunol. 2019 Jul;204:57-63. doi: 10.1016/j.clim.2018.11.001. Epub 2018 Nov 8.
32	Restimulation-induced T-cell death through NTB-A/SAP signaling pathway is impaired in tuberculosis patients with depressed immune responses.Immunol Cell Biol. 2017 Sep;95(8):716-728. doi: 10.1038/icb.2017.42. Epub 2017 May 26.
33	Differential expression of Candida albicans secreted aspartyl proteinase in human vulvovaginal candidiasis.Mycoses. 2007 Sep;50(5):383-90. doi: 10.1111/j.1439-0507.2007.01384.x.
34	Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood. 2000 Nov 1;96(9):3118-25.
35	Invasion of Candida albicans correlates with expression of secreted aspartic proteinases during experimental infection of human epidermis.J Invest Dermatol. 2000 Apr;114(4):712-7. doi: 10.1046/j.1523-1747.2000.00935.x.
36	Function of SLAM-Associated Protein (SAP) in Acute Pneumoseptic Bacterial Infection.J Mol Biol. 2019 Oct 4;431(21):4345-4353. doi: 10.1016/j.jmb.2019.07.002. Epub 2019 Jul 8.
37	Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death.Respir Physiol Neurobiol. 2018 Oct;256:43-49. doi: 10.1016/j.resp.2017.08.003. Epub 2017 Aug 16.
38	Interferon-gamma induces chronic active myocarditis and cardiomyopathy in transgenic mice.Am J Pathol. 2007 Aug;171(2):463-72. doi: 10.2353/ajpath.2007.060906. Epub 2007 Jun 7.
39	High expression of CD244 and SAP regulated CD8 T cell responses of patients with HTLV-I associated neurologic disease.PLoS Pathog. 2009 Dec;5(12):e1000682. doi: 10.1371/journal.ppat.1000682. Epub 2009 Dec 4.
40	The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation.Blood. 2013 Apr 25;121(17):3386-95. doi: 10.1182/blood-2012-11-468868. Epub 2013 Feb 21.
41	Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
42	Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
43	Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
44	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.