Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA3Z5LE)

• DOT Name: KICSTOR subunit 2 (KICS2)
• Synonyms: KICSTOR complex protein C12orf66
• Gene Name: KICS2
• UniProt ID: KICS2_HUMAN
• Pfam ID: PF09404
• Sequence:
  MGESIPLAAPVPVEQAVLETFFSHLGIFSYDKAKDNVEKEREANKSAGGSWLSLLAALAH
  LAAAEKVYHSLTYLGQKLGGQSFFSRKDSIRTIYTSLHNELKKVVTGRGALGGTAPHVEE
  LLSHLSEQLCFFVQARMEIADFYEKMYTLSTQKFINAEELVGLLDAIMKKYSSRFHHPIL
  SPLESSFQLEVDVLCHLLKAQAQVSEWKFLPSLVNLHSAHTKLQTWGQIFEKQRETKKHL
  FGGQSQKAVQPPHLFLWLMKLKNMLLAKFSFYFHEALSRQTTASEMKTLTAKANPDFFGK
  ISSFIRKYDAANVSLIFDNRGSESFQGHGYHHPHSYREAPKGVDQYPAVVSLPSDRPVMH
  WPNVIMIMTDRTSDLNSLEKVVHFYDDKVQSTYFLTRPEPHFTIVIIFESKKSERDSHFI
  SFLNEVSLALKNPKVFASLKPGAKG
• Function: As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose.
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

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 KICSTOR subunit 2 (KICS2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of KICSTOR subunit 2 (KICS2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of KICSTOR subunit 2 (KICS2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of KICSTOR subunit 2 (KICS2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of KICSTOR subunit 2 (KICS2).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of KICSTOR subunit 2 (KICS2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of KICSTOR subunit 2 (KICS2).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of KICSTOR subunit 2 (KICS2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of KICSTOR subunit 2 (KICS2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of KICSTOR subunit 2 (KICS2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of KICSTOR subunit 2 (KICS2).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of KICSTOR subunit 2 (KICS2).	[12]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.