Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPS43MQ)

• DOT Name: GATOR2 complex protein MIOS (MIOS)
• Synonyms: Missing oocyte meiosis regulator homolog
• Gene Name: MIOS
• UniProt ID: MIOS_HUMAN
• PDB ID: 7UHY
• Pfam ID: PF21719 ; PF21720 ; PF17034
• Sequence:
  MSGTKPDILWAPHHVDRFVVCDSELSLYHVESTVNSELKAGSLRLSEDSAATLLSINSDT
  PYMKCVAWYLNYDPECLLAVGQANGRVVLTSLGQDHNSKFKDLIGKEFVPKHARQCNTLA
  WNPLDSNWLAAGLDKHRADFSVLIWDICSKYTPDIVPMEKVKLSAGETETTLLVTKPLYE
  LGQNDACLSLCWLPRDQKLLLAGMHRNLAIFDLRNTSQKMFVNTKAVQGVTVDPYFHDRV
  ASFYEGQVAIWDLRKFEKPVLTLTEQPKPLTKVAWCPTRTGLLATLTRDSNIIRLYDMQH
  TPTPIGDETEPTIIERSVQPCDNYIASFAWHPTSQNRMIVVTPNRTMSDFTVFERISLAW
  SPITSLMWACGRHLYECTEEENDNSLEKDIATKMRLRALSRYGLDTEQVWRNHILAGNED
  PQLKSLWYTLHFMKQYTEDMDQKSPGNKGSLVYAGIKSIVKSSLGMVESSRHNWSGLDKQ
  SDIQNLNEERILALQLCGWIKKGTDVDVGPFLNSLVQEGEWERAAAVALFNLDIRRAIQI
  LNEGASSEKGDLNLNVVAMALSGYTDEKNSLWREMCSTLRLQLNNPYLCVMFAFLTSETG
  SYDGVLYENKVAVRDRVAFACKFLSDTQLNRYIEKLTNEMKEAGNLEGILLTGLTKDGVD
  LMESYVDRTGDVQTASYCMLQGSPLDVLKDERVQYWIENYRNLLDAWRFWHKRAEFDIHR
  SKLDPSSKPLAQVFVSCNFCGKSISYSCSAVPHQGRGFSQYGVSGSPTKSKVTSCPGCRK
  PLPRCALCLINMGTPVSSCPGGTKSDEKVDLSKDKKLAQFNNWFTWCHNCRHGGHAGHML
  SWFRDHAECPVSACTCKCMQLDTTGNLVPAETVQP
• Function: As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway. The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex. GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1. In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation. In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex. Within the GATOR2 complex, MIOS is required to prevent autoubiquitination of WDR24, the catalytic subunit of the complex. The GATOR2 complex is required for brain myelination.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of GATOR2 complex protein MIOS (MIOS).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GATOR2 complex protein MIOS (MIOS).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GATOR2 complex protein MIOS (MIOS).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GATOR2 complex protein MIOS (MIOS).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of GATOR2 complex protein MIOS (MIOS).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of GATOR2 complex protein MIOS (MIOS).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of GATOR2 complex protein MIOS (MIOS).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of GATOR2 complex protein MIOS (MIOS).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of GATOR2 complex protein MIOS (MIOS).	[9]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of GATOR2 complex protein MIOS (MIOS).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of GATOR2 complex protein MIOS (MIOS).	[10]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.