Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7G4ZYO)

• DOT Name: Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2)
• Synonyms: Cellular arginine sensor for mTORC1 protein 2; GATS-like protein 2
• Gene Name: CASTOR2
• Related Disease: Kaposi sarcoma
• UniProt ID: CAST2_HUMAN
• Pfam ID: PF13840 ; PF21389 ; PF18700
• Sequence:
  MELHILEHRLQVASVAKESIPLFTYGLIKLAFLSSKTRCKFFSLTETPEDYTIIVDEEGF
  LELPSSEHLSVADATWLALNVVSGGGSFSSSQPIGVTKIAKSVIAPLADQNISVFMLSTY
  QTDFILVRERDLPFVTHTLSSEFTILRVVNGETVAAENLGITNGFVKPKLVQRPVIHPLS
  SPSNRFCVTSLDPDTLPAVATLLMDVMFYSNGVKDPMATGDDCGHIRFFSFSLIEGYISL
  VMDVQTQQRFPSNLLFTSASGELWKMVRIGGQPLGFDECGIVAQISEPLAAADIPAYYIS
  TFKFDHALVPEENINGVISALKVSQAEKH
• Function: Functions as a negative regulator of the TORC1 signaling pathway through the GATOR complex. As part of homodimers or heterodimers with CASTOR1, directly binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1. Does not directly bind arginine, but binding of arginine to CASTOR1 disrupts the interaction of CASTOR2-containing heterodimers 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2).	[3]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytosolic arginine sensor for mTORC1 subunit 2 (CASTOR2).	[5]

References

• [1] 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.
• [2] 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.
• [3] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [4] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [5] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [6] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [7] 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.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.