Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH562MY)

• DOT Name: SH2 domain-containing protein 4A (SH2D4A)
• Synonyms: Protein SH(2)A; Protein phosphatase 1 regulatory subunit 38
• Gene Name: SH2D4A
• Related Disease:
  Hepatocellular carcinoma
  Liver cirrhosis
  Neoplasm
• UniProt ID: SH24A_HUMAN
• Pfam ID: PF00017
• Sequence:
  MLKQILSEMYIDPDLLAELSEEQKQILFFKMREEQIRRWKEREAAMERKESLPVKPRPKK
  ENGKSVHWKLGADKEVWVWVMGEHHLDKPYDVLCNEIIAERARLKAEQEAEEPRKTHSEE
  FTNSLKTKSQYHDLQAPDNQQTKDIWKKVAEKEELEQGSRPAPTLEEEKIRSLSSSSRNI
  QQMLADSINRMKAYAFHQKKESMKKKQDEEINQIEEERTKQICKSWKEDSEWQASLRKSK
  AADEKRRSLAKQAREDYKRLSLGAQKGRGGERLQSPLRVPQKPERPPLPPKPQFLNSGAY
  PQKPLRNQGVVRTLSSSAQEDIIRWFKEEQLPLRAGYQKTSDTIAPWFHGILTLKKANEL
  LLSTGMPGSFLIRVSERIKGYALSYLSEDGCKHFLIDASADAYSFLGVDQLQHATLADLV
  EYHKEEPITSLGKELLLYPCGQQDQLPDYLELFE
• Function: Inhibits estrogen-induced cell proliferation by competing with PLCG for binding to ESR1, blocking the effect of estrogen on PLCG and repressing estrogen-induced proliferation. May play a role in T-cell development and function.
• Tissue Specificity: Ubiquitously expressed. Aberrantly expressed in some cancers.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of SH2 domain-containing protein 4A (SH2D4A).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of SH2 domain-containing protein 4A (SH2D4A).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of SH2 domain-containing protein 4A (SH2D4A).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SH2 domain-containing protein 4A (SH2D4A).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of SH2 domain-containing protein 4A (SH2D4A).	[14]

2 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 increases the methylation of SH2 domain-containing protein 4A (SH2D4A).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of SH2 domain-containing protein 4A (SH2D4A).	[15]

References

• [1] Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma.Hepatology. 2016 Sep;64(3):828-42. doi: 10.1002/hep.28684. Epub 2016 Jul 15.
• [2] Constant serum levels of secreted asialoglycoprotein receptor sH2a and decrease with cirrhosis.World J Gastroenterol. 2011 Dec 28;17(48):5305-9. doi: 10.3748/wjg.v17.i48.5305.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] 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.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.