Details of Drug Off-Target (DOT)

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

• DOT Name: SH2B adapter protein 2 (SH2B2)
• Synonyms: Adapter protein with pleckstrin homology and Src homology 2 domains; SH2 and PH domain-containing adapter protein APS
• Gene Name: SH2B2
• Related Disease:
  Intellectual disability
  Nephropathy
  Adult respiratory distress syndrome
  Advanced cancer
  Alopecia
  Attention deficit hyperactivity disorder
  Autoimmune disease
  Chondrosarcoma
  Coagulation defect
  Cryopyrin-associated periodic syndrome
  Graves disease
  Lupus
  Phospholipid syndrome
  Prostate cancer
  Prostate carcinoma
  Thrombocytopenia
  Thrombophilia
  Vitiligo
  Addison disease
  Autoimmune polyendocrinopathy
  Female hypogonadism
  Stroke
  Endocrine disease
  leukaemia
  Leukemia
  Psychotic disorder
  Systemic lupus erythematosus
  Type-1/2 diabetes
  Vascular disease
• UniProt ID: SH2B2_HUMAN
• PDB ID: 1Q2H
• Pfam ID: PF00169 ; PF08916 ; PF00017
• Sequence:
  MNGAGPGPAAAAPVPVPVPVPDWRQFCELHAQAAAVDFAHKFCRFLRDNPAYDTPDAGAS
  FSRHFAANFLDVFGEEVRRVLVAGPTTRGAAVSAEAMEPELADTSALKAAPYGHSRSSED
  VSTHAATKARVRKGFSLRNMSLCVVDGVRDMWHRRASPEPDAAAAPRTAEPRDKWTRRLR
  LSRTLAAKVELVDIQREGALRFMVADDAAAGSGGSAQWQKCRLLLRRAVAEERFRLEFFV
  PPKASRPKVSIPLSAIIEVRTTMPLEMPEKDNTFVLKVENGAEYILETIDSLQKHSWVAD
  IQGCVDPGDSEEDTELSCTRGGCLASRVASCSCELLTDAVDLPRPPETTAVGAVVTAPHS
  RGRDAVRESLIHVPLETFLQTLESPGGSGSDSNNTGEQGAETDPEAEPELELSDYPWFHG
  TLSRVKAAQLVLAGGPRNHGLFVIRQSETRPGEYVLTFNFQGKAKHLRLSLNGHGQCHVQ
  HLWFQSVLDMLRHFHTHPIPLESGGSADITLRSYVRAQDPPPEPGPTPPAAPASPACWSD
  SPGQHYFSSLAAAACPPASPSDAAGASSSSASSSSAASGPAPPRPVEGQLSARSRSNSAE
  RLLEAVAATAAEEPPEAAPGRARAVENQYSFY
• Function: Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways. May be involved in coupling from immunoreceptor to Ras signaling. Acts as a negative regulator of cytokine signaling in collaboration with CBL. Binds to EPOR and suppresses EPO-induced STAT5 activation, possibly through a masking effect on STAT5 docking sites in EPOR. Suppresses PDGF-induced mitogenesis. May induce cytoskeletal reorganization via interaction with VAV3.
• Tissue Specificity: Expressed in spleen, prostate, testis, uterus, small intestine and skeletal muscle. Among hematopoietic cell lines, expressed exclusively in B-cells. Not expressed in most tumor cell lines.
• Reactome Pathway:
  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

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Nephropathy	DISXWP4P	Definitive	Biomarker	[2]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Alopecia	DIS37HU4	Strong	Biomarker	[5]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Biomarker	[7]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[8]
Coagulation defect	DIS9X3H6	Strong	Biomarker	[9]
Cryopyrin-associated periodic syndrome	DISPXXOZ	Strong	Genetic Variation	[10]
Graves disease	DISU4KOQ	Strong	Biomarker	[5]
Lupus	DISOKJWA	Strong	Biomarker	[11]
Phospholipid syndrome	DISPI49U	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[13]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[13]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[14]
Thrombophilia	DISQR7U7	Strong	Genetic Variation	[15]
Vitiligo	DISR05SL	Strong	Biomarker	[5]
Addison disease	DIS7HNOH	moderate	Biomarker	[16]
Autoimmune polyendocrinopathy	DISOLDB2	moderate	Biomarker	[17]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[18]
Stroke	DISX6UHX	moderate	Biomarker	[11]
Endocrine disease	DISRGY2N	Limited	Genetic Variation	[19]
leukaemia	DISS7D1V	Limited	Biomarker	[20]
Leukemia	DISNAKFL	Limited	Biomarker	[20]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[21]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[22]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[23]
Vascular disease	DISVS67S	Limited	Biomarker	[17]

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 2 (SH2B2).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SH2B adapter protein 2 (SH2B2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SH2B adapter protein 2 (SH2B2).	[25]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of SH2B adapter protein 2 (SH2B2).	[27]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of SH2B adapter protein 2 (SH2B2).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of SH2B adapter protein 2 (SH2B2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of SH2B adapter protein 2 (SH2B2).	[30]

References

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• [2] Kidney disease in primary anti-phospholipid antibody syndrome.Rheumatology (Oxford). 2017 Jul 1;56(7):1069-1080. doi: 10.1093/rheumatology/kew307.
• [3] Catastrophic antiphospholipid (Asherson's) syndrome and genetic thrombophilic disorders in obstetrics.Autoimmun Rev. 2006 Dec;6(2):89-93. doi: 10.1016/j.autrev.2006.06.011. Epub 2006 Jul 24.
• [4] Association studies of serum prostate-specific antigen levels and the genetic polymorphisms at the androgen receptor and prostate-specific antigen genes.Cancer Epidemiol Biomarkers Prev. 2002 Jul;11(7):664-9.
• [5] HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III.Horm Metab Res. 2003 Feb;35(2):120-4. doi: 10.1055/s-2003-39059.
• [6] Screening for Attention-Deficit/Hyperactivity Disorder and Comorbidities in a Diverse, Urban Primary Care Setting.Clin Pediatr (Phila). 2018 Oct;57(12):1442-1452. doi: 10.1177/0009922818787329. Epub 2018 Jul 13.
• [7] Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry.Rheumatology (Oxford). 2020 Aug 1;59(8):2043-2051. doi: 10.1093/rheumatology/kez562.
• [8] Identification and differential expression of human collagenase-3 mRNA species derived from internal deletion, alternative splicing, and different polyadenylation and transcription initiation sites.Osteoarthritis Cartilage. 2003 Jul;11(7):524-37. doi: 10.1016/s1063-4584(03)00079-7.
• [9] Coagulopathy triggered autoimmunity: experimental antiphospholipid syndrome in factor V Leiden mice.BMC Med. 2013 Apr 4;11:92. doi: 10.1186/1741-7015-11-92.
• [10] Catastrophic antiphospholipid syndrome: an update.Panminerva Med. 2017 Sep;59(3):254-268. doi: 10.23736/S0031-0808.17.03324-9. Epub 2017 May 8.
• [11] Clinical and immunological features of antiphospholipid syndrome in the elderly: a retrospective national multicentre study.Rheumatology (Oxford). 2019 Jun 1;58(6):1006-1010. doi: 10.1093/rheumatology/key437.
• [12] The comparison of real world and core laboratory antiphospholipid antibody ELISA results from antiphospholipid syndrome alliance for clinical trials & international networking (APS ACTION) clinical database and repository analysis.Thromb Res. 2019 Mar;175:32-36. doi: 10.1016/j.thromres.2019.01.010. Epub 2019 Jan 18.
• [13] Polymorphisms in the androgen receptor and the prostate-specific antigen genes and prostate cancer risk.Prostate. 2005 Sep 15;65(1):58-65. doi: 10.1002/pros.20230.
• [14] Identifying phenotypes of patients with antiphospholipid antibodies: results from a cluster analysis in a large cohort of patients.Rheumatology (Oxford). 2021 Mar 2;60(3):1106-1113. doi: 10.1093/rheumatology/kez596.
• [15] Direct oral anticoagulant use in patients with thrombophilia, antiphospholipid syndrome or venous thrombosis of unusual sites: A narrative review.Blood Rev. 2018 Jul;32(4):272-279. doi: 10.1016/j.blre.2018.01.002. Epub 2018 Apr 20.
• [16] Addison's disease: a survey on 633 patients in Padova.Eur J Endocrinol. 2013 Oct 21;169(6):773-84. doi: 10.1530/EJE-13-0528. Print 2013 Dec.
• [17] Neutrophil extracellular trap release is associated with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome.Rheumatology (Oxford). 2018 Jul 1;57(7):1228-1234. doi: 10.1093/rheumatology/key067.
• [18] Premature ovarian failure in patients with autoimmune Addison's disease: clinical, genetic, and immunological evaluation.J Clin Endocrinol Metab. 2011 Aug;96(8):E1255-61. doi: 10.1210/jc.2011-0414. Epub 2011 Jun 15.
• [19] Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population.Horm Res. 2005;64(5):253-60. doi: 10.1159/000089293. Epub 2005 Oct 27.
• [20] Structure characterization and anti-leukemia activity of a novel polysaccharide from Angelica sinensis (Oliv.) Diels.Int J Biol Macromol. 2019 Jan;121:161-172. doi: 10.1016/j.ijbiomac.2018.09.213. Epub 2018 Oct 2.
• [21] Diagnostic and Prognostic Significance of DSM-5 Attenuated Psychosis Syndrome in Services for Individuals at Ultra High Risk for Psychosis.Schizophr Bull. 2018 Feb 15;44(2):264-275. doi: 10.1093/schbul/sbx055.
• [22] Apoptosis in patients with primary antiphospholipid antibody syndrome.Int J Rheum Dis. 2019 Apr;22(4):677-685. doi: 10.1111/1756-185X.13468. Epub 2019 Feb 6.
• [23] Modulation of trophoblast function by concurrent hyperglycemia and antiphospholipid antibodies is in part TLR4-dependent.Am J Reprod Immunol. 2018 Oct;80(4):e13045. doi: 10.1111/aji.13045. Epub 2018 Sep 8.
• [24] 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.
• [25] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [26] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [27] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [28] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [29] 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.
• [30] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.