Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOA45GL)

DOT Name	Spermatogenesis-associated protein 2 (SPATA2)
Gene Name	SPATA2
Related Disease	Adenocarcinoma ( ) Adult lymphoma ( ) Autoimmune disease ( ) B-cell neoplasm ( ) Brain neoplasm ( ) Breast carcinoma ( ) Carcinoma of esophagus ( ) Clear cell renal carcinoma ( ) Endometrial cancer ( ) Endometrial carcinoma ( ) Epithelial ovarian cancer ( ) Esophageal cancer ( ) Head-neck squamous cell carcinoma ( ) Hepatitis B virus infection ( ) Hepatitis C virus infection ( ) HIV infectious disease ( ) Immunodeficiency ( ) Lung adenocarcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Lymphoma ( ) Multiple sclerosis ( ) Neoplasm of esophagus ( ) Nephropathy ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Pediatric lymphoma ( ) Plasma cell myeloma ( ) Prostate cancer ( ) Prostate carcinoma ( ) Psoriasis ( ) Pulmonary fibrosis ( ) Renal cell carcinoma ( ) Rheumatoid arthritis ( ) Systemic lupus erythematosus ( ) Triple negative breast cancer ( ) Type-1 diabetes ( ) Colorectal carcinoma ( ) Kidney cancer ( ) Small-cell lung cancer ( ) Adult glioblastoma ( ) Glioblastoma multiforme ( ) Pancreatic ductal carcinoma ( ) Breast cancer ( ) Hepatocellular carcinoma ( ) Malignant soft tissue neoplasm ( ) Melanoma ( ) Neoplasm ( ) Sarcoma ( )
UniProt ID	SPAT2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5LJM; 5LJN
Pfam ID	PF21388
Sequence	MGKPSSMDTKFKDDLFRKYVQFHESKVDTTTSRQRPGSDECLRVAASTLLSLHKVDPFYR FRLIQFYEVVESSLRSLSSSSLRALHGAFSMLETVGINLFLYPWKKEFRSIKTYTGPFVY YVKSTLLEEDIRAILSCMGYTPELGTAYKLRELVETLQVKMVSFELFLAKVECEQMLEIH SQVKDKGYSELDIVSERKSSAEDVRGCSDALRRRAEGREHLTASMSRVALQKSASERAAK DYYKPRVTKPSRSVDAYDSYWESRKPPLKASLSLRKEPVATDVGDDLKDEIIRPSPSLLT MASSPHGSPDVLPPASPSNGPALLRGTYFSTQDDVDLYTDSEPRATYRRQDALRPDVWLL RNDAHSLYHKRSPPAKESALSKCQSCGLSCSSSLCQRCDSLLTCPPASKPSAFPSKASTH DSLAHGASLREKYPGQTQGLDRLPHLHSKSKPSTTPTSRCGFCNRPGATNTCTQCSKVSC DACLSAYHYDPCYKKSELHKFMPNNQLNYKSTQLSHLVYR
Function	Bridging factor that mediates the recruitment of CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced necroptosis. Acts as a direct binding intermediate that bridges RNF31/HOIP, the catalytic subunit of the LUBAC complex, and the deubiquitinase (CYLD), thereby recruiting CYLD to the TNF-R1 signaling complex (TNF-RSC). Required to activate the 'Met-1'- (linear) and 'Lys-63'-linked deubiquitinase activities of CYLD. Controls the kinase activity of RIPK1 and TNF-alpha-induced necroptosis by promoting 'Met-1'-linked deubiquitination of RIPK1 by CYLD.
Tissue Specificity	Present at high level in Sertoli cells, but not detected in spermatogenic cells (at protein level) . Low expression in spleen, thymus and prostate .
KEGG Pathway	Necroptosis (hsa04217 )
Reactome Pathway	Regulation of TNFR1 signaling (R-HSA-5357905 ) TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956 ) TNFR1-induced proapoptotic signaling (R-HSA-5357786 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[10]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[11]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[13]
HIV infectious disease	DISO97HC	Strong	Biomarker	[14]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[15]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[16]
Lung cancer	DISCM4YA	Strong	Biomarker	[17]
Lung carcinoma	DISTR26C	Strong	Biomarker	[17]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[18]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[7]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[19]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[10]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[10]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[20]
Prostate cancer	DISF190Y	Strong	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[21]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[22]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[23]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[24]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[25]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[26]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[27]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[28]
Kidney cancer	DISBIPKM	moderate	Biomarker	[29]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[30]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[31]
Glioblastoma multiforme	DISK8246	Disputed	Altered Expression	[31]
Pancreatic ductal carcinoma	DIS26F9Q	Disputed	Altered Expression	[32]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[33]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Biomarker	[34]
Melanoma	DIS1RRCY	Limited	Biomarker	[35]
Neoplasm	DISZKGEW	Limited	Biomarker	[36]
Sarcoma	DISZDG3U	Limited	Biomarker	[34]
------------------------------------------------------------------------------------


⏷ Show the Full List of 49 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

8 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 Spermatogenesis-associated protein 2 (SPATA2).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Spermatogenesis-associated protein 2 (SPATA2).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Spermatogenesis-associated protein 2 (SPATA2).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Spermatogenesis-associated protein 2 (SPATA2).	[40]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Spermatogenesis-associated protein 2 (SPATA2).	[41]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Spermatogenesis-associated protein 2 (SPATA2).	[43]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Spermatogenesis-associated protein 2 (SPATA2).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Spermatogenesis-associated protein 2 (SPATA2).	[46]
------------------------------------------------------------------------------------


⏷ Show the Full List of 8 Drug(s)

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Spermatogenesis-associated protein 2 (SPATA2).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Spermatogenesis-associated protein 2 (SPATA2).	[44]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Spermatogenesis-associated protein 2 (SPATA2).	[47]
------------------------------------------------------------------------------------

References

1	Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma.Cancer Immunol Res. 2015 Oct;3(10):1123-1129. doi: 10.1158/2326-6066.CIR-15-0046. Epub 2015 Jun 16.
2	Adoptive transfer of murine T cells expressing a chimeric-PD1-Dap10 receptor as an immunotherapy for lymphoma.Immunology. 2017 Nov;152(3):472-483. doi: 10.1111/imm.12784. Epub 2017 Jul 27.
3	PD-1/PD-L and autoimmunity: A growing relationship.Cell Immunol. 2016 Dec;310:27-41. doi: 10.1016/j.cellimm.2016.09.009. Epub 2016 Sep 15.
4	Therapeutic Efficacy of 4-1BB Costimulation Is Abrogated by PD-1 Blockade in a Model of Spontaneous B-cell Lymphoma.Cancer Immunol Res. 2017 Mar;5(3):191-197. doi: 10.1158/2326-6066.CIR-16-0249. Epub 2017 Jan 23.
5	Association of PD-1.5 C/T, but Not PD-1.3 G/A, with Malignant and Benign Brain Tumors in Iranian Patients.Immunol Invest. 2017 Jul;46(5):469-480. doi: 10.1080/08820139.2017.1296858. Epub 2017 May 23.
6	PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model.BMC Cancer. 2018 Jun 19;18(1):669. doi: 10.1186/s12885-018-4412-8.
7	PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer.Cell Physiol Biochem. 2017;42(6):2267-2280. doi: 10.1159/000480000. Epub 2017 Aug 17.
8	Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) expression in fumarate hydratase-deficient renal cell carcinoma.Ann Diagn Pathol. 2017 Aug;29:17-22. doi: 10.1016/j.anndiagpath.2017.04.007. Epub 2017 Apr 24.
9	Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1.JAMA Oncol. 2015 Dec;1(9):1319-23. doi: 10.1001/jamaoncol.2015.2151.
10	Tumor necrosis factor receptor modulator spermatogenesis-associated protein 2 is a novel predictor of outcome in ovarian cancer.Cancer Sci. 2019 Mar;110(3):1117-1126. doi: 10.1111/cas.13955. Epub 2019 Feb 16.
11	Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti-PD-1 Resistance in Head and Neck Cancer.Clin Cancer Res. 2020 Jan 1;26(1):290-300. doi: 10.1158/1078-0432.CCR-19-1351. Epub 2019 Sep 27.
12	PD-1 mRNA expression is associated with clinical and viral profile and PD1 3'-untranslated region polymorphism in patients with chronic HBV infection.Immunol Lett. 2014 Nov;162(1 Pt A):212-6. doi: 10.1016/j.imlet.2014.09.001. Epub 2014 Sep 9.
13	A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.PLoS One. 2013 May 22;8(5):e63818. doi: 10.1371/journal.pone.0063818. Print 2013.
14	Cutting edge: Prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells.J Immunol. 2013 Jul 15;191(2):540-4. doi: 10.4049/jimmunol.1203161. Epub 2013 Jun 14.
15	Feline programmed death and its ligand: characterization and changes with feline immunodeficiency virus infection.Vet Immunol Immunopathol. 2010 Mar 15;134(1-2):107-14. doi: 10.1016/j.vetimm.2009.10.019. Epub 2009 Oct 14.
16	Association of PD-1 polymorphisms with the risk and prognosis of lung adenocarcinoma in the northeastern Chinese Han population.BMC Med Genet. 2019 Nov 12;20(1):177. doi: 10.1186/s12881-019-0914-8.
17	The changing face of cancer treatments.BMJ Case Rep. 2018 Sep 1;2018:bcr2018224784. doi: 10.1136/bcr-2018-224784.
18	Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
19	A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients.Lupus. 2004;13(7):510-6. doi: 10.1191/0961203303lu1052oa.
20	Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma.Blood. 2017 Sep 7;130(10):1189-1197. doi: 10.1182/blood-2017-03-775122. Epub 2017 May 1.
21	The Immune Checkpoint Regulator PDL1 is an Independent Prognostic Biomarker for Biochemical Recurrence in Prostate Cancer Patients Following Adjuvant Hormonal Therapy.J Cancer. 2019 Jun 2;10(14):3102-3111. doi: 10.7150/jca.30384. eCollection 2019.
22	Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.Am J Hum Genet. 2015 Jan 8;96(1):104-20. doi: 10.1016/j.ajhg.2014.12.004.
23	Characterization of CD28(null) T cells in idiopathic pulmonary fibrosis.Mucosal Immunol. 2019 Jan;12(1):212-222. doi: 10.1038/s41385-018-0082-8. Epub 2018 Oct 12.
24	Extracellular Vesicles Transfer the Receptor Programmed Death-1 in Rheumatoid Arthritis.Front Immunol. 2017 Jul 24;8:851. doi: 10.3389/fimmu.2017.00851. eCollection 2017.
25	Effects of the programmed cell death 1 (PDCD1) polymorphisms in susceptibility to systemic lupus erythematosus.Int J Immunogenet. 2020 Feb;47(1):57-64. doi: 10.1111/iji.12456. Epub 2019 Sep 29.
26	PD1 protein expression in tumor infiltrated lymphocytes rather than PDL1 in tumor cells predicts survival in triple-negative breast cancer.Cancer Biol Ther. 2018 May 4;19(5):373-380. doi: 10.1080/15384047.2018.1423919. Epub 2018 Feb 16.
27	PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children.Hum Genet. 2007 Apr;121(2):223-32. doi: 10.1007/s00439-006-0309-8. Epub 2007 Jan 3.
28	Integrating Immunotherapy Into Colorectal Cancer Care.Oncology (Williston Park). 2018 Oct 15;32(10):494-8.
29	A Rationally Designed Peptide Antagonist of the PD-1 Signaling Pathway as an Immunomodulatory Agent for Cancer Therapy.Mol Cancer Ther. 2019 Jun;18(6):1081-1091. doi: 10.1158/1535-7163.MCT-18-0737. Epub 2019 Apr 23.
30	Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer.Cancer Res. 2018 Aug 1;78(15):4270-4281. doi: 10.1158/0008-5472.CAN-17-2176. Epub 2018 May 18.
31	PD-L1/PD-1 Axis in Glioblastoma Multiforme.Int J Mol Sci. 2019 Oct 28;20(21):5347. doi: 10.3390/ijms20215347.
32	IFN- down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer.BMC Cancer. 2019 Nov 6;19(1):1053. doi: 10.1186/s12885-019-6145-8.
33	Programmed Death Receptor 1 (PD1) Knockout and Human Telomerase Reverse Transcriptase (hTERT) Transduction Can Enhance Persistence and Antitumor Efficacy of Cytokine-Induced Killer Cells Against Hepatocellular Carcinoma.Med Sci Monit. 2018 Jul 3;24:4573-4582. doi: 10.12659/MSM.910903.
34	Emerging Targeted and Immune-Based Therapies in Sarcoma.J Clin Oncol. 2018 Jan 10;36(2):125-135. doi: 10.1200/JCO.2017.75.1610. Epub 2017 Dec 8.
35	Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism.Am J Emerg Med. 2017 Jul;35(7):1039.e5-1039.e7. doi: 10.1016/j.ajem.2017.02.048. Epub 2017 Feb 27.
36	Osteosarcoma cell intrinsic PD-L2 signals promote invasion and metastasis via the RhoA-ROCK-LIMK2 and autophagy pathways.Cell Death Dis. 2019 Mar 18;10(4):261. doi: 10.1038/s41419-019-1497-1.
37	Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
38	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
39	Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
40	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.
41	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
42	Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
43	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
44	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.
45	Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
46	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.
47	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.