Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZG59LW)

• DOT Name: SH2 domain-containing protein 1B (SH2D1B)
• Synonyms: EWS/FLI1-activated transcript 2; EAT-2
• Gene Name: SH2D1B
• Related Disease:
  Ewing sarcoma
  Neoplasm
• UniProt ID: SH21B_HUMAN
• PDB ID: 5KAZ
• Pfam ID: PF00017
• Sequence:
  MDLPYYHGRLTKQDCETLLLKEGVDGNFLLRDSESIPGVLCLCVSFKNIVYTYRIFREKH
  GYYRIQTAEGSPKQVFPSLKELISKFEKPNQGMVVHLLKPIKRTSPSLRWRGLKLELETF
  VNSNSDYVDVLP
• Function: Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as CD84, SLAMF1, LY9 and CD244. In SLAM signaling seems to cooperate with SH2D1A/SAP. Plays a role in regulation of effector functions of natural killer (NK) cells by controlling signal transduction through CD244/2B4 without effecting its tyrosine phosphorylation; downstream signaling involves PLCG1 and ERK activation. Activation of SLAMF7-mediated NK cell function does not effect receptor tyrosine phosphorylation but distal signaling. In the context of NK cell-mediated cytotoxicity does not enhance conjugate formation with target cells but stimulates polarization of the microtubule-organizing center and cytotoxic granules toward the NK cell synapse. Negatively regulates CD40-induced cytokine production in dendritic cells downstream of SLAM family receptors probably by inducing activation of the PI3K pathway to inhibit p38 MAPK and JNK activation.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of SH2 domain-containing protein 1B (SH2D1B).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of SH2 domain-containing protein 1B (SH2D1B).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH2 domain-containing protein 1B (SH2D1B).	[6]

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 increases the methylation of SH2 domain-containing protein 1B (SH2D1B).	[5]

References

• [1] NK cell recognition of hematopoietic cells by SLAM-SAP families.Cell Mol Immunol. 2019 May;16(5):452-459. doi: 10.1038/s41423-019-0222-4. Epub 2019 Mar 25.
• [2] EAT-2 is a novel SH2 domain containing protein that is up regulated by Ewing's sarcoma EWS/FLI1 fusion gene.Oncogene. 1996 Dec 19;13(12):2649-58.
• [3] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [5] 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.
• [6] 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.