Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXC0JXR)

• DOT Name: Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9)
• Synonyms: v-ATPase assembly regulator TMEM9; Dermal papilla-derived protein 4; Transmembrane protein 9; Protein TMEM9
• Gene Name: TMEM9
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Colorectal carcinoma
  Familial adenomatous polyposis
  Hepatocellular carcinoma
  Liver cancer
• UniProt ID: TMEM9_HUMAN
• Pfam ID: PF05434
• Sequence:
  MKLLSLVAVVGCLLVPPAEANKSSEDIRCKCICPPYRNISGHIYNQNVSQKDCNCLHVVE
  PMPVPGHDVEAYCLLCECRYEERSTTTIKVIIVIYLSVVGALLLYMAFLMLVDPLIRKPD
  AYTEQLHNEEENEDARSMAAAAASLGGPRANTVLERVEGAQQRWKLQVQEQRKTVFDRHK
  MLS
• Function: Transmembrane protein that binds to and facilitates the assembly of lysosomal proton-transporting V-type ATPase (v-ATPase), resulting in enhanced lysosomal acidification and trafficking. By bringing the v-ATPase accessory protein ATP6AP2 and the v-ATPase subunit ATP6V0D1 together, allows v-ATPase complex formation and activation. TMEM9-controlled vesicular acidification induces hyperactivation of Wnt/beta-catenin signaling, involved in development, tissue homeostasis and tissue regeneration, through lysosomal degradation of adenomatous polyposis coli/APC. In the liver, involved in hepatic regeneration.
• Tissue Specificity: Highly expressed in adrenal gland, thyroid gland, testis, ovary and prostate . Moderate expression in trachea, spinal cord, stomach, colon, small intestine and spleen . Low expression in bone marrow, lymph node, thymus and peripheral blood lymphocytes . Expression is detected in hematopoietic cell lines including those of myeloid, erythroid, B- and T-cell origin .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Liver cancer	DISDE4BI	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9) affects the response to substance of Acetaminophen.	[11]

6 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 Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Proton-transporting V-type ATPase complex assembly regulator TMEM9 (TMEM9).	[9]

References

• [1] Effects of TMEM9 gene on cell progression in hepatocellular carcinoma by RNA interference.Oncol Rep. 2016 Jul;36(1):299-305. doi: 10.3892/or.2016.4821. Epub 2016 May 19.
• [2] TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/-catenin signalling.Nat Cell Biol. 2018 Dec;20(12):1421-1433. doi: 10.1038/s41556-018-0219-8. Epub 2018 Oct 29.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] 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.
• [6] 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.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] 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.
• [10] 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.
• [11] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.