Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPAV531)

• DOT Name: Transmembrane 4 L6 family member 5 (TM4SF5)
• Synonyms: Tetraspan transmembrane protein L6H
• Gene Name: TM4SF5
• Related Disease:
  Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome
  Colorectal carcinoma
  Hepatocellular carcinoma
  Lung neoplasm
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Pancreatic tumour
  Pulmonary fibrosis
  Colon cancer
  Colon carcinoma
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Neoplasm
• UniProt ID: T4S5_HUMAN
• Pfam ID: PF05805
• Sequence:
  MCTGKCARCVGLSLITLCLVCIVANALLLVPNGETSWTNTNHLSLQVWLMGGFIGGGLMV
  LCPGIAAVRAGGKGCCGAGCCGNRCRMLRSVFSSAFGVLGAIYCLSVSGAGLRNGPRCLM
  NGEWGYHFEDTAGAYLLNRTLWDRCEAPPRVVPWNVTLFSLLVAASCLEIVLCGIQLVNA
  TIGVFCGDCRKKQDTPH
• Function: Acts as a lysosomal membrane arginine sensor. Forms a complex with MTOR and SLC38A9 on lysosomal membranes in an arginine-regulated manner, leading to arginine efflux which enables the activation of mTORC1 which subsequently leads to RPS6KB1 and EIF4EBP1 phosphorylations. Facilitates cell cycle G1/S phase progression and the translocation of the CDK4-CCND1 complex into the nucleus. CDKN1B and RHOA/ROCK signaling activity are involved in TM4SF5-mediated acceleration of G1/S phase progression.
• Tissue Specificity: Intestine. Overexpressed in pancreatic cancers.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome	DISRVSZF	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Lung neoplasm	DISVARNB	Strong	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Pancreatic cancer	DISJC981	Strong	Biomarker	[7]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[7]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[1]
Colon cancer	DISVC52G	moderate	Biomarker	[2]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[9]
Liver cancer	DISDE4BI	Limited	Altered Expression	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]

2 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 Transmembrane 4 L6 family member 5 (TM4SF5).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transmembrane 4 L6 family member 5 (TM4SF5).	[15]

5 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 Transmembrane 4 L6 family member 5 (TM4SF5).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane 4 L6 family member 5 (TM4SF5).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transmembrane 4 L6 family member 5 (TM4SF5).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Transmembrane 4 L6 family member 5 (TM4SF5).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transmembrane 4 L6 family member 5 (TM4SF5).	[16]

References

• [1] TM4SF5-mediated CD44v8-10 splicing variant promotes survival of type II alveolar epithelial cells during idiopathic pulmonary fibrosis.Cell Death Dis. 2019 Sep 9;10(9):645. doi: 10.1038/s41419-019-1878-5.
• [2] Production of an anti-TM4SF5 monoclonal antibody and its application in the detection of TM4SF5 as a possible marker of a poor prognosis in colorectal cancer.Int J Oncol. 2018 Jul;53(1):275-285. doi: 10.3892/ijo.2018.4385. Epub 2018 Apr 26.
• [3] Transmembrane 4L Six Family Member 5 Senses Arginine for mTORC1 Signaling.Cell Metab. 2019 Jun 4;29(6):1306-1319.e7. doi: 10.1016/j.cmet.2019.03.005. Epub 2019 Apr 4.
• [4] Identification of genes associated with the corticotroph phenotype in bronchial carcinoid tumors.J Clin Endocrinol Metab. 2002 Nov;87(11):5015-22. doi: 10.1210/jc.2002-020598.
• [5] Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells.J Cell Sci. 2012 Dec 15;125(Pt 24):5960-73. doi: 10.1242/jcs.100586. Epub 2012 Oct 17.
• [6] Bidirectional signaling between TM4SF5 and IGF1R promotes resistance to EGFR kinase inhibitors.Lung Cancer. 2015 Oct;90(1):22-31. doi: 10.1016/j.lungcan.2015.06.023. Epub 2015 Jul 2.
• [7] A peptide-CpG-DNA-liposome complex vaccine targeting TM4SF5 suppresses growth of pancreatic cancer in a mouse allograft model.Onco Targets Ther. 2018 Dec 3;11:8655-8672. doi: 10.2147/OTT.S186606. eCollection 2018.
• [8] Clinicopathological significance of TM4SF5 expression in human hepatocellular carcinoma tissues.Oncol Lett. 2019 Jun;17(6):5187-5192. doi: 10.3892/ol.2019.10210. Epub 2019 Apr 3.
• [9] CD133-induced TM4SF5 expression promotes sphere growth via recruitment and blocking of protein tyrosine phosphatase receptor type F (PTPRF).Cancer Lett. 2018 Dec 1;438:219-231. doi: 10.1016/j.canlet.2018.09.009. Epub 2018 Sep 11.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [15] 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.
• [16] 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.