Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSF44KP)

• DOT Name: Src kinase-associated phosphoprotein 2 (SKAP2)
• Synonyms: Pyk2/RAFTK-associated protein; Retinoic acid-induced protein 70; SKAP55 homolog; SKAP-55HOM; SKAP-HOM; Src family-associated phosphoprotein 2; Src kinase-associated phosphoprotein 55-related protein; Src-associated adapter protein with PH and SH3 domains
• Gene Name: SKAP2
• Related Disease:
  Leukocyte adhesion deficiency type 1
  Multiple sclerosis
  Non-small-cell lung cancer
  Schizophrenia
  Type-1 diabetes
  Inflammatory bowel disease
  Adenocarcinoma
  Ankylosing spondylitis
  Crohn disease
  Gallbladder cancer
  Gallbladder carcinoma
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Osteoarthritis
  Prostate cancer
  Prostate carcinoma
  Psoriasis
  Psychotic disorder
  Sclerosing cholangitis
  Systemic lupus erythematosus
  Ulcerative colitis
• UniProt ID: SKAP2_HUMAN
• PDB ID: 3OMH
• Pfam ID: PF00169 ; PF00018
• Sequence:
  MPNPSSTSSPYPLPEEIRNLLADVETFVADILKGENLSKKAKEKRESLIKKIKDVKSIYL
  QEFQDKGDAEDGEEYDDPFAGPPDTISLASERYDKDDEAPSDGAQFPPIAAQDLPFVLKA
  GYLEKRRKDHSFLGFEWQKRWCALSKTVFYYYGSDKDKQQKGEFAIDGYSVRMNNTLRKD
  GKKDCCFEISAPDKRIYQFTAASPKDAEEWVQQLKFVLQDMESDIIPEDYDERGELYDDV
  DHPLPISNPLTSSQPIDDEIYEELPEEEEDSAPVKVEEQRKMSQDSVHHTSGDKSTDYAN
  FYQGLWDCTGAFSDELSFKRGDVIYILSKEYNRYGWWVGEMKGAIGLVPKAYIMEMYDI
• Function: May be involved in B-cell and macrophage adhesion processes. In B-cells, may act by coupling the B-cell receptor (BCR) to integrin activation. May play a role in src signaling pathway.
• Tissue Specificity: Ubiquitously expressed. Present in platelets (at protein level).
• KEGG Pathway: Yersinia infection (hsa05135)
• Reactome Pathway: Signal regulatory protein family interactions (R-HSA-391160)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukocyte adhesion deficiency type 1	DISA1J7W	Strong	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[5]
Inflammatory bowel disease	DISGN23E	moderate	Genetic Variation	[6]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[7]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[8]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[8]
Gallbladder cancer	DISXJUAF	Limited	Altered Expression	[9]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[9]
Lung cancer	DISCM4YA	Limited	Biomarker	[10]
Lung carcinoma	DISTR26C	Limited	Biomarker	[10]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[7]
Osteoarthritis	DIS05URM	Limited	Biomarker	[11]
Prostate cancer	DISF190Y	Limited	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[12]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[8]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[13]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[8]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[14]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[8]

21 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 Src kinase-associated phosphoprotein 2 (SKAP2).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[23]
Marinol	DM70IK5	Approved	Marinol increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[24]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[25]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[25]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[28]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[32]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Src kinase-associated phosphoprotein 2 (SKAP2).	[33]

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 Src kinase-associated phosphoprotein 2 (SKAP2).	[30]

References

• [1] Skap2 is required for (2) integrin-mediated neutrophil recruitment and functions.J Exp Med. 2017 Mar 6;214(3):851-874. doi: 10.1084/jem.20160647. Epub 2017 Feb 9.
• [2] 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.
• [3] Src kinase-associated phosphoprotein2 expression is associated with poor prognosis in non-small cell lung cancer.Anticancer Res. 2015 Apr;35(4):2411-5.
• [4] Dietary patterns and physical activity in people with schizophrenia and increased waist circumference.Schizophr Res. 2018 Sep;199:109-115. doi: 10.1016/j.schres.2018.03.016. Epub 2018 Mar 16.
• [5] Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.Nat Genet. 2009 Jun;41(6):703-7. doi: 10.1038/ng.381. Epub 2009 May 10.
• [6] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [7] Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays.Oncogene. 2008 Mar 20;27(13):1951-60. doi: 10.1038/sj.onc.1210832. Epub 2007 Oct 22.
• [8] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [9] UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest.Oncol Rep. 2014 Jun;31(6):2635-43. doi: 10.3892/or.2014.3145. Epub 2014 Apr 23.
• [10] SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression.Cancer Res. 2016 Jan 15;76(2):358-69. doi: 10.1158/0008-5472.CAN-15-1879. Epub 2015 Nov 17.
• [11] Identification of Novel Genes in Osteoarthritic Fibroblast-Like Synoviocytes Using Next-Generation Sequencing and Bioinformatics Approaches.Int J Med Sci. 2019 Jul 21;16(8):1057-1071. doi: 10.7150/ijms.35611. eCollection 2019.
• [12] Prevalence of the HOXB13 G84E mutation among unaffected men with a family history of prostate cancer.J Genet Couns. 2014 Jun;23(3):371-6. doi: 10.1007/s10897-013-9672-5. Epub 2013 Dec 7.
• [13] Reduced integrity of superior longitudinal fasciculus and arcuate fasciculus as a marker for auditory hallucinations in schizophrenia: A DTI tractography study.Asian J Psychiatr. 2019 Aug;44:179-186. doi: 10.1016/j.ajp.2019.07.043. Epub 2019 Jul 30.
• [14] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [15] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [16] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [17] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [18] 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.
• [19] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] 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.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [24] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [25] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [26] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] 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.
• [29] 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.
• [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] 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.
• [32] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [33] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.