Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXTOD10)

• DOT Name: Tether containing UBX domain for GLUT4 (ASPSCR1)
• Synonyms: Alveolar soft part sarcoma chromosomal region candidate gene 1 protein; Alveolar soft part sarcoma locus; Renal papillary cell carcinoma protein 17; UBX domain-containing protein 9
• Gene Name: ASPSCR1
• Related Disease:
  Parkinson disease
  Rheumatoid arthritis
  Advanced cancer
  Carcinoma
  Depression
  Fragile X-associated tremor/ataxia syndrome
  Hyperinsulinemia
  Intervertebral disc degeneration
  Kidney neoplasm
  Neoplasm
  Neuroblastoma
  Obesity
  Osteoarthritis
  Renal cell carcinoma
  Sarcoma
  Sleep disorder
  Soft tissue neoplasm
  Alveolar soft part sarcoma
  Soft tissue sarcoma
  Bone osteosarcoma
  Clear cell renal carcinoma
  Malignant soft tissue neoplasm
  Osteosarcoma
  Type-1/2 diabetes
• UniProt ID: ASPC1_HUMAN
• PDB ID: 5IFS; 5IFW; 7OAT
• Pfam ID: PF11470 ; PF00789
• Sequence:
  MAAPAGGGGSAVSVLAPNGRRHTVKVTPSTVLLQVLEDTCRRQDFNPCEYDLKFQRSVLD
  LSLQWRFANLPNNAKLEMVPASRSREGPENMVRIALQLDDGSRLQDSFCSGQTLWELLSH
  FPQIRECLQHPGGATPVCVYTRDEVTGEAALRGTTLQSLGLTGGSATIRFVMKCYDPVGK
  TPGSLGSSASAGQAAASAPLPLESGELSRGDLSRPEDADTSGPCCEHTQEKQSTRAPAAA
  PFVPFSGGGQRLGGPPGPTRPLTSSSAKLPKSLSSPGGPSKPKKSKSGQDPQQEQEQERE
  RDPQQEQERERPVDREPVDREPVVCHPDLEERLQAWPAELPDEFFELTVDDVRRRLAQLK
  SERKRLEEAPLVTKAFREAQIKEKLERYPKVALRVLFPDRYVLQGFFRPSETVGDLRDFV
  RSHLGNPELSFYLFITPPKTVLDDHTQTLFQANLFPAALVHLGAEEPAGVYLEPGLLEHA
  ISPSAADVLVARYMSRAAGSPSPLPAPDPAPKSEPAAEEGALVPPEPIPGTAQPVKRSLG
  KVPKWLKLPASKR
• Function: Tethering protein that sequesters GLUT4-containing vesicles in the cytoplasm in the absence of insulin. Modulates the amount of GLUT4 that is available at the cell surface. Enhances VCP methylation catalyzed by VCPKMT.
• Tissue Specificity: Ubiquitous. Highly expressed in testis, heart, skeletal muscle and pancreas.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway: Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Fragile X-associated tremor/ataxia syndrome	DISKB25R	Strong	Biomarker	[6]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[7]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[8]
Kidney neoplasm	DISBNZTN	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Osteoarthritis	DIS05URM	Strong	Biomarker	[12]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[13]
Sarcoma	DISZDG3U	Strong	Altered Expression	[14]
Sleep disorder	DIS3JP1U	Strong	Altered Expression	[15]
Soft tissue neoplasm	DISP2OHE	Strong	Genetic Variation	[16]
Alveolar soft part sarcoma	DISLKJKZ	moderate	Genetic Variation	[17]
Soft tissue sarcoma	DISSN8XB	moderate	Altered Expression	[14]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[10]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[13]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Biomarker	[18]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[19]

4 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 Tether containing UBX domain for GLUT4 (ASPSCR1).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tether containing UBX domain for GLUT4 (ASPSCR1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tether containing UBX domain for GLUT4 (ASPSCR1).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Tether containing UBX domain for GLUT4 (ASPSCR1).	[28]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tether containing UBX domain for GLUT4 (ASPSCR1).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tether containing UBX domain for GLUT4 (ASPSCR1).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tether containing UBX domain for GLUT4 (ASPSCR1).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tether containing UBX domain for GLUT4 (ASPSCR1).	[25]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tether containing UBX domain for GLUT4 (ASPSCR1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tether containing UBX domain for GLUT4 (ASPSCR1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Tether containing UBX domain for GLUT4 (ASPSCR1).	[29]

References

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• [2] Sarcopenia in osteoarthritis and rheumatoid arthritis: The association with self-reported fatigue, physical function and obesity.PLoS One. 2019 Jun 6;14(6):e0217462. doi: 10.1371/journal.pone.0217462. eCollection 2019.
• [3] Second Reported Case of Pediatric Bladder Alveolar Soft Part Sarcoma as Secondary Malignancy After Prior Cytotoxic Chemotherapy.Urology. 2019 Aug;130:148-150. doi: 10.1016/j.urology.2019.04.002. Epub 2019 Apr 12.
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• [5] Overall benefits provided by orthopedic surgical intervention in patients with rheumatoid arthritis.Mod Rheumatol. 2019 Mar;29(2):335-343. doi: 10.1080/14397595.2018.1457468. Epub 2018 Apr 16.
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• [7] Glucose Responsiveness of -Cells Depends on Fatty Acids.Exp Clin Endocrinol Diabetes. 2020 Oct;128(10):644-653. doi: 10.1055/a-0884-2919. Epub 2019 Apr 15.
• [8] Assessment of the Minimum Clinically Important Difference in the Timed Up and Go Test After Surgery for Lumbar Degenerative Disc Disease.Neurosurgery. 2017 Mar 1;80(3):380-385. doi: 10.1227/NEU.0000000000001320.
• [9] Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents.Am J Pathol. 2001 Jul;159(1):179-92. doi: 10.1016/S0002-9440(10)61684-7.
• [10] LncRNA TUG1 promotes cell proliferation and suppresses apoptosis in osteosarcoma by regulating miR-212-3p/FOXA1 axis.Biomed Pharmacother. 2018 Jan;97:1645-1653. doi: 10.1016/j.biopha.2017.12.004. Epub 2017 Dec 8.
• [11] The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat.EMBO Mol Med. 2018 Mar;10(3):e8047. doi: 10.15252/emmm.201708047.
• [12] Effects of Elastic Resistance Exercise After Total Knee Replacement on Muscle Mass and Physical Function in Elderly Women With Osteoarthritis: A Randomized Controlled Trial.Am J Phys Med Rehabil. 2020 May;99(5):381-389. doi: 10.1097/PHM.0000000000001344.
• [13] Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma with a micropapillary pattern: cases report and literature review.Am J Transl Res. 2019 Jan 15;11(1):327-339. eCollection 2019.
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• [15] Modifiable factors affecting older patients' quality of life and physical function during cancer treatment.J Geriatr Oncol. 2019 Nov;10(6):904-912. doi: 10.1016/j.jgo.2019.08.001. Epub 2019 Aug 21.
• [16] Detection of the ASPSCR1-TFE3 gene fusion in paraffin-embedded alveolar soft part sarcomas.Histopathology. 2007 Jun;50(7):881-6. doi: 10.1111/j.1365-2559.2007.02693.x.
• [17] Lingual Alveolar Soft Part Sarcoma in a 1-Year-Old Infant: Youngest Reported Case With Characteristic ASPSCR1-TFE3 Fusion.Pediatr Dev Pathol. 2019 Jul-Aug;22(4):391-395. doi: 10.1177/1093526619830290. Epub 2019 Feb 11.
• [18] MET overexpressing chordomas frequently exhibit polysomy of chromosome 7 but no MET activation through sarcoma-specific gene fusions.Tumour Biol. 2010 Jun;31(3):157-63. doi: 10.1007/s13277-010-0021-0. Epub 2010 Mar 6.
• [19] Impaired balance is related to the progression of diabetic complications in both young and older adults.J Diabetes Complications. 2017 Aug;31(8):1275-1282. doi: 10.1016/j.jdiacomp.2017.05.014. Epub 2017 Jun 4.
• [20] 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.
• [21] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] 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.
• [24] 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.
• [25] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] 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.
• [28] 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.
• [29] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.