Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT90JNBS)

• DOT Name: SH3 domain-binding protein 2 (SH3BP2)
• Synonyms: 3BP-2
• Gene Name: SH3BP2
• Related Disease:
  Arthritis
  Autoimmune disease
  Bladder cancer
  Bone disease
  Cherubism
  Chronic recurrent multifocal osteomyelitis
  Clear cell renal carcinoma
  Giant cell tumor
  Huntington disease
  Leukemia
  Lupus
  Majeed syndrome
  Multiple sclerosis
  Renal cell carcinoma
  Systemic lupus erythematosus
  Urinary bladder cancer
  Urinary bladder neoplasm
  Gastrointestinal stromal tumour
  Lupus nephritis
  Neoplasm
  Neurofibromatosis type 1
  Periodontal disease
  Periodontitis
  Rheumatoid arthritis
• UniProt ID: 3BP2_HUMAN
• PDB ID: 2CR4; 3TWR
• Pfam ID: PF00169 ; PF00017
• Sequence:
  MAAEEMHWPVPMKAIGAQNLLTMPGGVAKAGYLHKKGGTQLQLLKWPLRFVIIHKRCVYY
  FKSSTSASPQGAFSLSGYNRVMRAAEETTSNNVFPFKIIHISKKHRTWFFSASSEEERKS
  WMALLRREIGHFHEKKDLPLDTSDSSSDTDSFYGAVERPVDISLSPYPTDNEDYEHDDED
  DSYLEPDSPEPGRLEDALMHPPAYPPPPVPTPRKPAFSDMPRAHSFTSKGPGPLLPPPPP
  KHGLPDVGLAAEDSKRDPLCPRRAEPCPRVPATPRRMSDPPLSTMPTAPGLRKPPCFRES
  ASPSPEPWTPGHGACSTSSAAIMATATSRNCDKLKSFHLSPRGPPTSEPPPVPANKPKFL
  KIAEEDPPREAAMPGLFVPPVAPRPPALKLPVPEAMARPAVLPRPEKPQLPHLQRSPPDG
  QSFRSFSFEKPRQPSQADTGGDDSDEDYEKVPLPNSVFVNTTESCEVERLFKATSPRGEP
  QDGLYCIRNSSTKSGKVLVVWDETSNKVRNYRIFEKDSKFYLEGEVLFVSVGSMVEHYHT
  HVLPSHQSLLLRHPYGYTGPR
• Function: Binds differentially to the SH3 domains of certain proteins of signal transduction pathways. Binds to phosphatidylinositols; linking the hemopoietic tyrosine kinase fes to the cytoplasmic membrane in a phosphorylation dependent mechanism.
• Tissue Specificity: Expressed in a variety of tissues including lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: .tural killer cell mediated cytotoxicity (hsa04650)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Bone disease	DISE1F82	Strong	Genetic Variation	[3]
Cherubism	DISHLJI0	Strong	Autosomal dominant	[4]
Chronic recurrent multifocal osteomyelitis	DIST1OU2	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Giant cell tumor	DIS8LOIN	Strong	Genetic Variation	[7]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Lupus	DISOKJWA	Strong	Biomarker	[1]
Majeed syndrome	DIS8AI2U	Strong	Genetic Variation	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[1]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[11]
Lupus nephritis	DISCVGPZ	moderate	Biomarker	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Neurofibromatosis type 1	DIS53JH9	moderate	Genetic Variation	[13]
Periodontal disease	DISJQHVN	Limited	Biomarker	[14]
Periodontitis	DISI9JOI	Limited	Biomarker	[14]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of SH3 domain-binding protein 2 (SH3BP2).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SH3 domain-binding protein 2 (SH3BP2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SH3 domain-binding protein 2 (SH3BP2).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[23]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[24]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[25]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of SH3 domain-binding protein 2 (SH3BP2).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of SH3 domain-binding protein 2 (SH3BP2).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SH3 domain-binding protein 2 (SH3BP2).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[29]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of SH3 domain-binding protein 2 (SH3BP2).	[31]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SH3 domain-binding protein 2 (SH3BP2).	[30]

References

• [1] Sh3bp2 Gain-Of-Function Mutation Ameliorates Lupus Phenotypes in B6.MRL-Fas(lpr) Mice.Cells. 2019 Apr 30;8(5):402. doi: 10.3390/cells8050402.
• [2] Identification and characterization of the human homologue of SH3BP2, an SH3 binding domain protein within a common region of deletion at 4p16.3 involved in bladder cancer.Genomics. 1997 Sep 1;44(2):163-70. doi: 10.1006/geno.1997.4849.
• [3] Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages.J Clin Invest. 2015 Apr;125(4):1396-400. doi: 10.1172/JCI71081. Epub 2015 Feb 23.
• [4] Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat Genet. 2001 Jun;28(2):125-6. doi: 10.1038/88832.
• [5] Autoinflammatory bone disorders.Curr Opin Rheumatol. 2007 Sep;19(5):492-8. doi: 10.1097/BOR.0b013e32825f5492.
• [6] Immunogenic properties of renal cell carcinoma and the pathogenesis of osteolytic bone metastases.Int J Oncol. 2009 May;34(5):1387-93.
• [7] Mutations in SH3BP2, the cherubism gene, were not detected in central or peripheral giant cell tumours of the jaw.Br J Oral Maxillofac Surg. 2008 Apr;46(3):229-230. doi: 10.1016/j.bjoms.2007.04.014. Epub 2007 Jun 4.
• [8] Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region.Am J Hum Genet. 2012 Mar 9;90(3):434-44. doi: 10.1016/j.ajhg.2012.01.005. Epub 2012 Mar 1.
• [9] Regulation of FcepsilonRI-mediated degranulation by an adaptor protein 3BP2 in rat basophilic leukemia RBL-2H3 cells.Blood. 2002 Sep 15;100(6):2138-44. doi: 10.1182/blood-2001-12-0340.
• [10] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [11] Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth.Mol Oncol. 2018 Aug;12(8):1383-1397. doi: 10.1002/1878-0261.12332. Epub 2018 Jun 30.
• [12] Effects of a spleen tyrosine kinase inhibitor on progression of the lupus nephritis in mice.J Pharmacol Sci. 2017 May;134(1):29-36. doi: 10.1016/j.jphs.2017.02.015. Epub 2017 Mar 25.
• [13] Neurofibromatosis presenting with a cherubism phenotype.Eur J Pediatr. 2007 Sep;166(9):905-9. doi: 10.1007/s00431-006-0334-6. Epub 2006 Nov 21.
• [14] Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts.J Bone Miner Res. 2020 Feb;35(2):382-395. doi: 10.1002/jbmr.3882. Epub 2019 Oct 24.
• [15] Loss of SH3 domain-binding protein 2 function suppresses bone destruction in tumor necrosis factor-driven and collagen-induced arthritis in mice.Arthritis Rheumatol. 2015 Mar;67(3):656-67. doi: 10.1002/art.38975.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [23] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [24] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [25] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [26] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.