Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOGB2BR)

• DOT Name: Hematopoietic SH2 domain-containing protein (HSH2D)
• Synonyms: Hematopoietic SH2 protein; Adaptor in lymphocytes of unknown function X
• Gene Name: HSH2D
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Cystic fibrosis
  Endometriosis
  Frontonasal dysplasia
  Intestinal disorder
  Pneumonia
  Pneumonitis
  Advanced cancer
  Osteoarthritis
  Adult lymphoma
  Asthma
  Lymphoma
  Pediatric lymphoma
• UniProt ID: HSH2D_HUMAN
• PDB ID: 2CS0
• Pfam ID: PF00017
• Sequence:
  MTEAGKLPLPLPPRLDWFVHTQMGQLAQDGVPEWFHGAISREDAENLLESQPLGSFLIRV
  SHSHVGYTLSYKAQSSCCHFMVKLLDDGTFMIPGEKVAHTSLDALVTFHQQKPIEPRREL
  LTQPCRQKDPANVDYEDLFLYSNAVAEEAACPVSAPEEASPKPVLCHQSKERKPSAEMNR
  ITTKEATSSCPPKSPLGETRQKLWRSLKMLPERGQRVRQQLKSHLATVNLSSLLDVRRST
  VISGPGTGKGSQDHSGDPTSGDRGYTDPCVATSLKSPSQPQAPKDRKVPTRKAERSVSCI
  EVTPGDRSWHQMVVRALSSQESKPEHQGLAEPENDQLPEEYQQPPPFAPGYC
• Function: May be a modulator of the apoptotic response through its ability to affect mitochondrial stability. Adapter protein involved in tyrosine kinase and CD28 signaling. Seems to affect CD28-mediated activation of the RE/AP element of the interleukin-2 promoter.
• Tissue Specificity: Predominantly expressed in spleen and hematopoietic cells such as peripheral blood leukocytes and weakly expressed in prostate, thymus, heart, small intestine and placenta.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[3]
Frontonasal dysplasia	DISXV4YX	Strong	Biomarker	[4]
Intestinal disorder	DISGPMUQ	Strong	Biomarker	[5]
Pneumonia	DIS8EF3M	Strong	Biomarker	[6]
Pneumonitis	DIS88E0K	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Osteoarthritis	DIS05URM	moderate	Biomarker	[8]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[9]
Asthma	DISW9QNS	Limited	Biomarker	[10]
Lymphoma	DISN6V4S	Limited	Biomarker	[9]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Hematopoietic SH2 domain-containing protein (HSH2D).	[18]

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 affects the methylation of Hematopoietic SH2 domain-containing protein (HSH2D).	[16]

References

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• [2] Activity of hypothiocyanite and lactoferrin (ALX-009) against respiratory cystic fibrosis pathogens in sputum.J Antimicrob Chemother. 2018 Dec 1;73(12):3391-3397. doi: 10.1093/jac/dky357.
• [3] Annexin A1, FPR2/ALX, and inflammatory cytokine expression in peritoneal endometriosis.J Reprod Immunol. 2018 Sep;129:30-35. doi: 10.1016/j.jri.2018.08.002. Epub 2018 Aug 3.
• [4] Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Am J Hum Genet. 2010 May 14;86(5):789-96. doi: 10.1016/j.ajhg.2010.04.002. Epub 2010 May 6.
• [5] Up-regulation of Annexin-A1 and lipoxin A(4) in individuals with ulcerative colitis may promote mucosal homeostasis.PLoS One. 2012;7(6):e39244. doi: 10.1371/journal.pone.0039244. Epub 2012 Jun 18.
• [6] Specialized Pro-Resolving Lipid Mediators Regulate Ozone-Induced Pulmonary and Systemic Inflammation.Toxicol Sci. 2018 Jun 1;163(2):466-477. doi: 10.1093/toxsci/kfy040.
• [7] Blocking "don't eat me" signal of CD47-SIRP in hematological malignancies, an in-depth review.Blood Rev. 2018 Nov;32(6):480-489. doi: 10.1016/j.blre.2018.04.005. Epub 2018 Apr 14.
• [8] Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain.Arthritis Rheumatol. 2017 May;69(5):996-1008. doi: 10.1002/art.40001.
• [9] The adaptor protein HSH2 attenuates apoptosis in response to ligation of the B cell antigen receptor complex on the B lymphoma cell line, WEHI-231.J Biol Chem. 2005 Feb 4;280(5):3507-15. doi: 10.1074/jbc.M407690200. Epub 2004 Nov 29.
• [10] ALX receptor ligands define a biochemical endotype for severe asthma.JCI Insight. 2017 Jul 20;2(14):e93534. doi: 10.1172/jci.insight.93534. eCollection 2017 Jul 20.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [16] 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.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.