Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYIH7WK)

• DOT Name: Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1)
• Synonyms: Cellular arginine sensor for mTORC1 protein 1; GATS-like protein 3
• Gene Name: CASTOR1
• Related Disease:
  Advanced cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Rheumatoid arthritis
  Kaposi sarcoma
• UniProt ID: CAST1_HUMAN
• PDB ID: 5GS9; 5GT7; 5GT8; 5GV2; 5I2C
• Pfam ID: PF13840 ; PF21389 ; PF18700
• Sequence:
  MELHILEHRVRVLSVARPGLWLYTHPLIKLLFLPRRSRCKFFSLTETPEDYTLMVDEEGF
  KELPPSEFLQVAEATWLVLNVSSHSGAAVQAAGVTKIARSVIAPLAEHHVSVLMLSTYQT
  DFILVREQDLSVVIHTLAQEFDIYREVGGEPVPVTRDDSSNGFPRTQHGPSPTVHPIQSP
  QNRFCVLTLDPETLPAIATTLIDVLFYSHSTPKEAASSSPEPSSITFFAFSLIEGYISIV
  MDAETQKKFPSDLLLTSSSGELWRMVRIGGQPLGFDECGIVAQIAGPLAAADISAYYIST
  FNFDHALVPEDGIGSVIEVLQRRQEGLAS
• Function: Functions as an intracellular arginine sensor within the amino acid-sensing branch of the TORC1 signaling pathway. As a homodimer or a heterodimer with CASTOR2, binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1. Binding of arginine to CASTOR1 allosterically disrupts the interaction of CASTOR1-containing dimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

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	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).	[7]

References

• [1] CASTOR1 suppresses the progression of lung adenocarcinoma and predicts poor prognosis.J Cell Biochem. 2018 Dec;119(12):10186-10194. doi: 10.1002/jcb.27360. Epub 2018 Aug 21.
• [2] Novel rheumatoid arthritis susceptibility locus at 22q12 identified in an extended UK genome-wide association study.Arthritis Rheumatol. 2014 Jan;66(1):24-30. doi: 10.1002/art.38196.
• [3] Kaposi sarcoma-associated herpesvirus miRNAs suppress CASTOR1-mediated mTORC1 inhibition to promote tumorigenesis.J Clin Invest. 2019 Jul 15;129(8):3310-3323. doi: 10.1172/JCI127166. eCollection 2019 Jul 15.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [6] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] 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.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.