Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8DNJSD)

• DOT Name: Target of rapamycin complex subunit LST8 (MLST8)
• Synonyms: TORC subunit LST8; G protein beta subunit-like; Gable; Protein GbetaL; Mammalian lethal with SEC13 protein 8; mLST8
• Gene Name: MLST8
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Esophageal squamous cell carcinoma
  Malignant glioma
  Neoplasm
  Sexually transmitted infection
  Visceral leishmaniasis
  Substance withdrawal syndrome
• UniProt ID: LST8_HUMAN
• PDB ID: 4JSN; 4JSP; 4JSV; 4JSX; 4JT5; 4JT6; 5FLC; 5H64; 5WBU; 5WBY; 5ZCS; 6BCU; 6BCX; 6SB0; 6SB2; 6ZWM; 6ZWO; 7OWG; 7PE7; 7PE8; 7PE9; 7PEA; 7PEB; 7PEC; 7TZO; 7UXC; 7UXH; 8ERA
• Pfam ID: PF00400
• Sequence:
  MNTSPGTVGSDPVILATAGYDHTVRFWQAHSGICTRTVQHQDSQVNALEVTPDRSMIAAA
  GYQHIRMYDLNSNNPNPIISYDGVNKNIASVGFHEDGRWMYTGGEDCTARIWDLRSRNLQ
  CQRIFQVNAPINCVCLHPNQAELIVGDQSGAIHIWDLKTDHNEQLIPEPEVSITSAHIDP
  DASYMAAVNSTGNCYVWNLTGGIGDEVTQLIPKTKIPAHTRYALQCRFSPDSTLLATCSA
  DQTCKIWRTSNFSLMTELSIKSGNPGESSRGWMWGCAFSGDSQYIVTASSDNLARLWCVE
  TGEIKREYGGHQKAVVCLAFNDSVLG
• Function: Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. In response to nutrients, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating several substrates, such as ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1). In the same time, it inhibits catabolic pathways by phosphorylating the autophagy initiation components ULK1 and ATG13, as well as transcription factor TFEB, a master regulators of lysosomal biogenesis and autophagy. The mTORC1 complex is inhibited in response to starvation and amino acid depletion. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'.
• Tissue Specificity: Broadly expressed, with highest levels in skeletal muscle, heart and kidney.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  Thermogenesis (hsa04714)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  MTOR signalling (R-HSA-165159)
  mTORC1-mediated signalling (R-HSA-166208)
  HSF1-dependent transactivation (R-HSA-3371571)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Regulation of TP53 Degradation (R-HSA-6804757)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Amino acids regulate mTORC1 (R-HSA-9639288)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[2]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[4]
Sexually transmitted infection	DISIVIAL	Strong	Biomarker	[5]
Visceral leishmaniasis	DISTKEYK	Strong	Biomarker	[6]
Substance withdrawal syndrome	DISTT24U	Limited	Biomarker	[7]

3 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 Target of rapamycin complex subunit LST8 (MLST8).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Target of rapamycin complex subunit LST8 (MLST8).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Target of rapamycin complex subunit LST8 (MLST8).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Target of rapamycin complex subunit LST8 (MLST8).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Target of rapamycin complex subunit LST8 (MLST8).	[19]

References

• [1] mLST8 Promotes mTOR-Mediated Tumor Progression.PLoS One. 2015 Apr 23;10(4):e0119015. doi: 10.1371/journal.pone.0119015. eCollection 2015.
• [2] Polymorphisms in mTORC1 genes modulate risk of esophageal squamous cell carcinoma in eastern Chinese populations.J Thorac Oncol. 2013 Jun;8(6):788-95. doi: 10.1097/JTO.0b013e31828916c6.
• [3] Epidermal growth factor receptor gene expression in high grade gliomas.Folia Neuropathol. 2011;49(1):28-38.
• [4] Disruption of the Scaffolding Function of mLST8 Selectively Inhibits mTORC2 Assembly and Function and Suppresses mTORC2-Dependent Tumor Growth In Vivo.Cancer Res. 2019 Jul 1;79(13):3178-3184. doi: 10.1158/0008-5472.CAN-18-3658. Epub 2019 May 13.
• [5] Men who have sex with men diagnosed with a sexually transmitted infection are significantly more likely to engage in sexualised drug use.Int J STD AIDS. 2017 Jan;28(1):91-93. doi: 10.1177/0956462416666753. Epub 2016 Aug 20.
• [6] The genetic structure of Leishmania infantum populations in Brazil and its possible association with the transmission cycle of visceral leishmaniasis.PLoS One. 2012;7(5):e36242. doi: 10.1371/journal.pone.0036242. Epub 2012 May 11.
• [7] Validation of the Withdrawal Assessment Tool-1 in Adult Intensive Care Patients.Am J Crit Care. 2019 Sep;28(5):361-369. doi: 10.4037/ajcc2019559.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] 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.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] 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.
• [17] 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.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.