Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTER0U8L)

• DOT Name: Ragulator complex protein LAMTOR5 (LAMTOR5)
• Synonyms: Hepatitis B virus X-interacting protein; HBV X-interacting protein; HBX-interacting protein; Late endosomal/lysosomal adaptor and MAPK and MTOR activator 5
• Gene Name: LAMTOR5
• Related Disease:
  Matthew-Wood syndrome
  Neoplasm
  Pancreatic ductal carcinoma
  Adenocarcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Esophageal squamous cell carcinoma
  Estrogen-receptor positive breast cancer
  Hepatitis B virus infection
  Liver cancer
  Metabolic disorder
  Non-small-cell lung cancer
  Tubular aggregate myopathy
  Hepatocellular carcinoma
• UniProt ID: LTOR5_HUMAN
• PDB ID: 3MS6; 3MSH; 5VOK; 5X6U; 5X6V; 5Y38; 5Y39; 5Y3A; 5YK3; 5YK5; 6B9X; 6EHP; 6EHR; 6NZD; 6U62; 6ULG; 6WJ2; 6WJ3; 7T3A; 7T3B; 7T3C; 7UX2; 7UXC; 7UXH; 8DHB
• Pfam ID: PF16672
• Sequence:
  MEATLEQHLEDTMKNPSIVGVLCTDSQGLNLGCRGTLSDEHAGVISVLAQQAAKLTSDPT
  DIPVVCLESDNGNIMIQKHDGITVAVHKMAS
• Function: As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway.
• Tissue Specificity: Highly expressed in skeletal and cardiac muscle, followed by pancreas, kidney, liver, brain, placenta and lung . Elevated levels in both cancerous and non-cancerous liver tissue of patients with chronic HBV infection compared with hepatic tissue without HBV infection .
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway:
  MTOR signalling (R-HSA-165159)
  mTORC1-mediated signalling (R-HSA-166208)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Amino acids regulate mTORC1 (R-HSA-9639288)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[6]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[6]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[8]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[9]
Liver cancer	DISDE4BI	Strong	Altered Expression	[4]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Tubular aggregate myopathy	DISC11WH	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ragulator complex protein LAMTOR5 (LAMTOR5).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ragulator complex protein LAMTOR5 (LAMTOR5).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ragulator complex protein LAMTOR5 (LAMTOR5).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ragulator complex protein LAMTOR5 (LAMTOR5).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ragulator complex protein LAMTOR5 (LAMTOR5).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Ragulator complex protein LAMTOR5 (LAMTOR5).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ragulator complex protein LAMTOR5 (LAMTOR5).	[17]

References

• [1] HBXIP protein overexpression predicts the poor prognosis of pancreatic ductal adenocarcinomas.Pathol Res Pract. 2019 Feb;215(2):343-346. doi: 10.1016/j.prp.2018.12.016. Epub 2018 Dec 12.
• [2] MiR-145-targeted HBXIP modulates human breast cancer cell proliferation.Thorac Cancer. 2019 Jan;10(1):71-77. doi: 10.1111/1759-7714.12903. Epub 2018 Oct 31.
• [3] LAMTOR5 raises abnormal initiation of O-glycosylation in breast cancer metastasis via modulating GALNT1 activity.Oncogene. 2020 Mar;39(11):2290-2304. doi: 10.1038/s41388-019-1146-2. Epub 2019 Dec 13.
• [4] Oncoprotein LAMTOR5 Activates GLUT1 Via Upregulating NF-B in Liver Cancer.Open Med (Wars). 2019 Feb 26;14:264-270. doi: 10.1515/med-2019-0022. eCollection 2019.
• [5] The oncoprotein HBXIP modulates the feedback loop of MDM2/p53 to enhance the growth of breast cancer.J Biol Chem. 2015 Sep 11;290(37):22649-61. doi: 10.1074/jbc.M115.658468. Epub 2015 Jul 30.
• [6] HBXIP over expression as an independent biomarker for cervical cancer.Exp Mol Pathol. 2017 Feb;102(1):133-137. doi: 10.1016/j.yexmp.2017.01.009. Epub 2017 Jan 16.
• [7] Elevated HBXIP expression is associated with aggressive phenotype and poor prognosis in esophageal squamous cell carcinoma.Am J Cancer Res. 2017 Nov 1;7(11):2190-2198. eCollection 2017.
• [8] Oncoprotein HBXIP enhances HOXB13 acetylation and co-activates HOXB13 to confer tamoxifen resistance in breast cancer.J Hematol Oncol. 2018 Feb 23;11(1):26. doi: 10.1186/s13045-018-0577-5.
• [9] Oncoprotein HBXIP induces PKM2 via transcription factor E2F1 to promote cell proliferation in ER-positive breast cancer.Acta Pharmacol Sin. 2019 Apr;40(4):530-538. doi: 10.1038/s41401-018-0015-9. Epub 2018 Jun 20.
• [10] The metabolic regulator Lamtor5 suppresses inflammatory signaling via regulating mTOR-mediated TLR4 degradation.Cell Mol Immunol. 2020 Oct;17(10):1063-1076. doi: 10.1038/s41423-019-0281-6. Epub 2019 Aug 29.
• [11] HBXIP suppression reduces cell proliferation and migration and its overexpression predicts poor prognosis in non-small-cell lung cancer.Tumour Biol. 2017 Jul;39(7):1010428317709675. doi: 10.1177/1010428317709675.
• [12] Pyridine nucleotide-disulphide oxidoreductase domain 2 (PYROXD2): Role in mitochondrial function.Mitochondrion. 2019 Jul;47:114-124. doi: 10.1016/j.mito.2019.05.007. Epub 2019 Jun 3.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.