Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2CEYTT)

• DOT Name: Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA)
• Synonyms: SHP substrate 1; SHPS-1; Brain Ig-like molecule with tyrosine-based activation motifs; Bit; CD172 antigen-like family member A; Inhibitory receptor SHPS-1; Macrophage fusion receptor; MyD-1 antigen; Signal-regulatory protein alpha-1; Sirp-alpha-1; Signal-regulatory protein alpha-2; Sirp-alpha-2; Signal-regulatory protein alpha-3; Sirp-alpha-3; p84; CD antigen CD172a
• Gene Name: SIRPA
• UniProt ID: SHPS1_HUMAN
• PDB ID: 2JJS; 2JJT; 2UV3; 2WNG; 4CMM; 6BIT; 6NMR; 6NMS; 6NMT; 6NMU; 6NMV; 7KPG; 7ST5; 7YGG
• Pfam ID: PF07654 ; PF07686
• Sequence:
  MEPAGPAPGRLGPLLCLLLAASCAWSGVAGEEELQVIQPDKSVLVAAGETATLRCTATSL
  IPVGPIQWFRGAGPGRELIYNQKEGHFPRVTTVSDLTKRNNMDFSIRIGNITPADAGTYY
  CVKFRKGSPDDVEFKSGAGTELSVRAKPSAPVVSGPAARATPQHTVSFTCESHGFSPRDI
  TLKWFKNGNELSDFQTNVDPVGESVSYSIHSTAKVVLTREDVHSQVICEVAHVTLQGDPL
  RGTANLSETIRVPPTLEVTQQPVRAENQVNVTCQVRKFYPQRLQLTWLENGNVSRTETAS
  TVTENKDGTYNWMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVSAHPKEQGSNT
  AAENTGSNERNIYIVVGVVCTLLVALLMAALYLVRIRQKKAQGSTSSTRLHEPEKNAREI
  TQDTNDITYADLNLPKGKKPAPQAAEPNNHTEYASIQTSPQPASEDTLTYADLDMVHLNR
  TPKQPAPKPEPSFSEYASVQVPRK
• Function: Immunoglobulin-like cell surface receptor for CD47. Acts as docking protein and induces translocation of PTPN6, PTPN11 and other binding partners from the cytosol to the plasma membrane. Supports adhesion of cerebellar neurons, neurite outgrowth and glial cell attachment. May play a key role in intracellular signaling during synaptogenesis and in synaptic function. Involved in the negative regulation of receptor tyrosine kinase-coupled cellular responses induced by cell adhesion, growth factors or insulin. Mediates negative regulation of phagocytosis, mast cell activation and dendritic cell activation. CD47 binding prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Plays a role in antiviral immunity and limits new world arenavirus infection by decreasing virus internalization. Receptor for THBS1. Interaction with THBS1 stimulates phosphorylation of SIRPA. In response to THBS1, involved in ROS signaling in non-phagocytic cells, stimulating NADPH oxidase-derived ROS production.
• Tissue Specificity: Ubiquitous. Highly expressed in brain. Detected on myeloid cells, but not T-cells. Detected at lower levels in heart, placenta, lung, testis, ovary, colon, liver, small intestine, prostate, spleen, kidney, skeletal muscle and pancreas.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Osteoclast differentiation (hsa04380)
• Reactome Pathway:
  Signal regulatory protein family interactions (R-HSA-391160)
  Neutrophil degranulation (R-HSA-6798695)
  Cell surface interactions at the vascular wall (R-HSA-202733)

Molecular Interaction Atlas (MIA) of This DOT

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 Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[13]

14 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 Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tyrosine-protein phosphatase non-receptor type substrate 1 (SIRPA).	[16]

References

• [1] 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.
• [2] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.