Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEB1VVI)

• DOT Name: Signal-transducing adaptor protein 2 (STAP2)
• Synonyms: STAP-2; Breast tumor kinase substrate; BRK substrate
• Gene Name: STAP2
• Related Disease:
  B-cell neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Diabetic retinopathy
  Dilated cardiomyopathy 1A
  Hyperglycemia
  Obesity
  Stroke
  Type-1/2 diabetes
  Diabetic neuropathy
  Cardiomyopathy
  Diabetic kidney disease
  Melanoma
  Non-insulin dependent diabetes
  Prediabetes syndrome
  Prostate cancer
  Prostate carcinoma
  Type-1 diabetes
• UniProt ID: STAP2_HUMAN
• PDB ID: 2EL8
• Sequence:
  MASALRPPRVPKPKGVLPSHYYESFLEKKGPCDRDYKKFWAGLQGLTIYFYNSNRDFQHV
  EKLNLGAFEKLTDEIPWGSSRDPGTHFSLILRDQEIKFKVETLECREMWKGFILTVVELR
  VPTDLTLLPGHLYMMSEVLAKEEARRALETPSCFLKVSRLEAQLLLERYPECGNLLLRPS
  GDGADGVSVTTRQMHNGTHVVRHYKVKREGPKYVIDVEQPFSCTSLDAVVNYFVSHTKKA
  LVPFLLDEDYEKVLGYVEADKENGENVWVAPSAPGPGPAPCTGGPKPLSPASSQDKLPPL
  PPLPNQEENYVTPIGDGPAVDYENQDVASSSWPVILKPKKLPKPPAKLPKPPVGPKPEPK
  VFNGGLGRKLPVSSAQPLFPTAGLADMTAELQKKLEKRRALEH
• Function: Substrate of protein kinase PTK6. May play a regulatory role in the acute-phase response in systemic inflammation and may modulate STAT3 activity.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  Cytoprotection by HMOX1 (R-HSA-9707564)
  PTK6 Activates STAT3 (R-HSA-8849474)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[3]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[5]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[6]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Genetic Variation	[8]
Stroke	DISX6UHX	Strong	Biomarker	[9]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[10]
Diabetic neuropathy	DISX6VF8	moderate	Biomarker	[11]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[12]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[13]
Melanoma	DIS1RRCY	Limited	Biomarker	[14]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[5]
Prediabetes syndrome	DISH2I53	Limited	Biomarker	[15]
Prostate cancer	DISF190Y	Limited	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[14]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[16]

11 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 Signal-transducing adaptor protein 2 (STAP2).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Signal-transducing adaptor protein 2 (STAP2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Signal-transducing adaptor protein 2 (STAP2).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Signal-transducing adaptor protein 2 (STAP2).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Signal-transducing adaptor protein 2 (STAP2).	[21]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Signal-transducing adaptor protein 2 (STAP2).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Signal-transducing adaptor protein 2 (STAP2).	[22]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Signal-transducing adaptor protein 2 (STAP2).	[23]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Signal-transducing adaptor protein 2 (STAP2).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Signal-transducing adaptor protein 2 (STAP2).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Signal-transducing adaptor protein 2 (STAP2).	[27]

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 decreases the methylation of Signal-transducing adaptor protein 2 (STAP2).	[25]

References

• [1] STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis.Oncogene. 2012 Oct 4;31(40):4384-96. doi: 10.1038/onc.2011.604. Epub 2012 Jan 9.
• [2] Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation.Oncotarget. 2017 May 9;8(19):30766-30780. doi: 10.18632/oncotarget.15403.
• [3] Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells.Cancer Sci. 2011 Apr;102(4):756-61. doi: 10.1111/j.1349-7006.2010.01842.x. Epub 2011 Jan 23.
• [4] Regulation of FcepsilonRI-mediated signaling by an adaptor protein STAP-2/BSK in rat basophilic leukemia RBL-2H3 cells.Biochem Biophys Res Commun. 2003 Jul 4;306(3):767-73. doi: 10.1016/s0006-291x(03)01042-8.
• [5] Mitochondrial uncoupling has no effect on microvascular complications in type 2 diabetes.Sci Rep. 2019 Jan 29;9(1):881. doi: 10.1038/s41598-018-37376-y.
• [6] Zinc Prevents the Development of Diabetic Cardiomyopathy in db/db Mice.Int J Mol Sci. 2017 Mar 7;18(3):580. doi: 10.3390/ijms18030580.
• [7] Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2',3,3'-Tetrabromo-4,4',5,5'-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice.Mol Pharm. 2019 May 6;16(5):1839-1850. doi: 10.1021/acs.molpharmaceut.8b01106. Epub 2019 Apr 18.
• [8] The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice.Int J Mol Sci. 2017 Oct 28;18(11):2268. doi: 10.3390/ijms18112268.
• [9] MiR-126 Mediates Brain Endothelial Cell Exosome Treatment-Induced Neurorestorative Effects After Stroke in Type 2 Diabetes Mellitus Mice.Stroke. 2019 Oct;50(10):2865-2874. doi: 10.1161/STROKEAHA.119.025371. Epub 2019 Aug 9.
• [10] Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair.Basic Res Cardiol. 2018 Oct 23;113(6):46. doi: 10.1007/s00395-018-0703-0.
• [11] Characterization of diabetic neuropathy progression in a mouse model of type 2 diabetes mellitus.Biol Open. 2018 Sep 5;7(9):bio036830. doi: 10.1242/bio.036830.
• [12] Cardioprotective effects of dietary rapamycin on adult female C57BLKS/J-Lepr(db) mice.Ann N Y Acad Sci. 2018 Apr;1418(1):106-117. doi: 10.1111/nyas.13557. Epub 2018 Jan 29.
• [13] Inhibition of Epidermal Growth Factor Receptor Activation Is Associated With Improved Diabetic Nephropathy and Insulin Resistance in Type 2 Diabetes.Diabetes. 2018 Sep;67(9):1847-1857. doi: 10.2337/db17-1513. Epub 2018 Jun 29.
• [14] STAP-2 protein promotes prostate cancer growth by enhancing epidermal growth factor receptor stabilization.J Biol Chem. 2017 Nov 24;292(47):19392-19399. doi: 10.1074/jbc.M117.802884. Epub 2017 Oct 6.
• [15] Reduced proliferation and a high apoptotic frequency of pancreatic beta cells contribute to genetically-determined diabetes susceptibility of db/db BKS mice.Horm Metab Res. 2011 May;43(5):306-11. doi: 10.1055/s-0031-1271817. Epub 2011 Mar 16.
• [16] Use of p53-Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease.J Am Heart Assoc. 2017 Apr 1;6(4):e005146. doi: 10.1161/JAHA.116.005146.
• [17] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [18] 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.
• [19] 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.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [22] 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.
• [23] 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.
• [24] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [25] 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.
• [26] MCM5 as a target of BET inhibitors in thyroid cancer cells. Endocr Relat Cancer. 2016 Apr;23(4):335-47. doi: 10.1530/ERC-15-0322. Epub 2016 Feb 24.
• [27] 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.