Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG93MCO)

• DOT Name: Ragulator complex protein LAMTOR3 (LAMTOR3)
• Synonyms: Late endosomal/lysosomal adaptor and MAPK and MTOR activator 3; MEK-binding partner 1; Mp1; Mitogen-activated protein kinase kinase 1-interacting protein 1; Mitogen-activated protein kinase scaffold protein 1
• Gene Name: LAMTOR3
• Related Disease:
  Advanced cancer
  Gastric cancer
  Stomach cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: LTOR3_HUMAN
• PDB ID: 1SKO; 2ZL1; 3CPT; 5X6U; 5X6V; 5Y39; 5Y3A; 5YK3; 6B9X; 6EHP; 6EHR; 6NZD; 6U62; 6ULG; 6WJ2; 6WJ3; 7T3A; 7T3B; 7T3C; 7UX2; 7UXC; 7UXH; 8DHB
• Pfam ID: PF08923
• Sequence:
  MADDLKRFLYKKLPSVEGLHAIVVSDRDGVPVIKVANDNAPEHALRPGFLSTFALATDQG
  SKLGLSKNKSIICYYNTYQVVQFNRLPLVVSFIASSSANTGLIVSLEKELAPLFEELRQV
  VEVS
• 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. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  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)
  MAP2K and MAPK activation (R-HSA-5674135)
  Neutrophil degranulation (R-HSA-6798695)
  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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[2]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[2]
Lung cancer	DISCM4YA	Limited	Biomarker	[3]
Lung carcinoma	DISTR26C	Limited	Biomarker	[3]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[4]

12 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 Ragulator complex protein LAMTOR3 (LAMTOR3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[15]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Ragulator complex protein LAMTOR3 (LAMTOR3).	[16]

References

• [1] Role of MEK partner-1 in cancer stemness through MEK/ERK pathway in cancerous neural stem cells, expressing EGFRviii.Mol Cancer. 2017 Aug 22;16(1):140. doi: 10.1186/s12943-017-0703-y.
• [2] A miR-29c binding site genetic variant in the 3'-untranslated region of LAMTOR3 gene is associated with gastric cancer risk.Biomed Pharmacother. 2015 Feb;69:70-5. doi: 10.1016/j.biopha.2014.11.008. Epub 2014 Nov 15.
• [3] BCL2 induced by LAMTOR3/MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer.Cancer Lett. 2017 Sep 10;403:48-58. doi: 10.1016/j.canlet.2017.05.019. Epub 2017 Jun 10.
• [4] Polymorphisms in the gene regions of the adaptor complex LAMTOR2/LAMTOR3 and their association with breast cancer risk.PLoS One. 2013;8(1):e53768. doi: 10.1371/journal.pone.0053768. Epub 2013 Jan 16.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.