Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD4ZKAL)

• DOT Name: Src kinase-associated phosphoprotein 1 (SKAP1)
• Synonyms: Src family-associated phosphoprotein 1; Src kinase-associated phosphoprotein of 55 kDa; SKAP-55; pp55
• Gene Name: SKAP1
• Related Disease:
  Anaplastic large cell lymphoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  Endometrial carcinoma
  Endometriosis
  Ovarian serous adenocarcinoma
• UniProt ID: SKAP1_HUMAN
• PDB ID: 1U5D
• Pfam ID: PF00169 ; PF14604
• Sequence:
  MQAAALPEEIRWLLEDAEEFLAEGLRNENLSAVARDHRDHILRGFQQIKARYYWDFQPQG
  GDIGQDSSDDNHSGTLGLSLTSDAPFLSDYQDEGMEDIVKGAQELDNVIKQGYLEKKSKD
  HSFFGSEWQKRWCVVSRGLFYYYANEKSKQPKGTFLIKGYGVRMAPHLRRDSKKESCFEL
  TSQDRRSYEFTATSPAEARDWVDQISFLLKDLSSLTIPYEEDEEEEEKEETYDDIDGFDS
  PSCGSQCRPTILPGSVGIKEPTEEKEEEDIYEVLPDEEHDLEEDESGTRRKGVDYASYYQ
  GLWDCHGDQPDELSFQRGDLIRILSKEYNMYGWWVGELNSLVGIVPKEYLTTAFEVEER
• Function: Positively regulates T-cell receptor signaling by enhancing the MAP kinase pathway. Required for optimal conjugation between T-cells and antigen-presenting cells by promoting the clustering of integrin ITGAL on the surface of T-cells. May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells.
• Tissue Specificity: Highly expressed in thymocytes and peripheral blood lymphocytes. Also expressed in spleen cells and testis. Present in T-cells (at protein level).
• KEGG Pathway: Rap1 sig.ling pathway (hsa04015)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[3]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[4]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Biomarker	[1]
Endometrial carcinoma	DISXR5CY	Limited	Genetic Variation	[5]
Endometriosis	DISX1AG8	Limited	Genetic Variation	[5]
Ovarian serous adenocarcinoma	DISSU72Z	Limited	Genetic Variation	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Src kinase-associated phosphoprotein 1 (SKAP1) affects the response to substance of Methotrexate.	[16]

9 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 Src kinase-associated phosphoprotein 1 (SKAP1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[13]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[14]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Src kinase-associated phosphoprotein 1 (SKAP1).	[15]

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 Src kinase-associated phosphoprotein 1 (SKAP1).	[11]

References

• [1] Intracellular TCR-signaling pathway: novel markers for lymphoma diagnosis and potential therapeutic targets.Am J Surg Pathol. 2014 Oct;38(10):1349-59. doi: 10.1097/PAS.0000000000000309.
• [2] Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth.Cancer Cell. 2015 Nov 9;28(5):569-581. doi: 10.1016/j.ccell.2015.09.021.
• [3] GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.Nat Genet. 2013 Apr;45(4):362-70, 370e1-2. doi: 10.1038/ng.2564.
• [4] Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.Nat Genet. 2017 May;49(5):680-691. doi: 10.1038/ng.3826. Epub 2017 Mar 27.
• [5] Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses.Cancer Med. 2018 May;7(5):1978-1987. doi: 10.1002/cam4.1445. Epub 2018 Apr 2.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] 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.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [14] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [15] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.
• [16] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.