Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0NLZ8I)

• DOT Name: KICSTOR complex protein ITFG2 (ITFG2)
• Synonyms: Integrin-alpha FG-GAP repeat-containing protein 2
• Gene Name: ITFG2
• UniProt ID: ITFG2_HUMAN
• Pfam ID: PF15907
• Sequence:
  MRSVSYVQRVALEFSGSLFPHAICLGDVDNDTLNELVVGDTSGKVSVYKNDDSRPWLTCS
  CQGMLTCVGVGDVCNKGKNLLVAVSAEGWFHLFDLTPAKVLDASGHHETLIGEEQRPVFK
  QHIPANTKVMLISDIDGDGCRELVVGYTDRVVRAFRWEELGEGPEHLTGQLVSLKKWMLE
  GQVDSLSVTLGPLGLPELMVSQPGCAYAILLCTWKKDTGSPPASEGPTDGSRETPAARDV
  VLHQTSGRIHNKNVSTHLIGNIKQGHGTESSGSGLFALCTLDGTLKLMEEMEEADKLLWS
  VQVDHQLFALEKLDVTGNGHEEVVACAWDGQTYIIDHNRTVVRFQVDENIRAFCAGLYAC
  KEGRNSPCLVYVTFNQKIYVYWEVQLERMESTNLVKLLETKPEYHSLLQELGVDPDDLPV
  TRALLHQTLYHPDQPPQCAPSSLQDPT
• 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

10 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 KICSTOR complex protein ITFG2 (ITFG2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of KICSTOR complex protein ITFG2 (ITFG2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of KICSTOR complex protein ITFG2 (ITFG2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of KICSTOR complex protein ITFG2 (ITFG2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of KICSTOR complex protein ITFG2 (ITFG2).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of KICSTOR complex protein ITFG2 (ITFG2).	[5]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of KICSTOR complex protein ITFG2 (ITFG2).	[5]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of KICSTOR complex protein ITFG2 (ITFG2).	[5]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of KICSTOR complex protein ITFG2 (ITFG2).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of KICSTOR complex protein ITFG2 (ITFG2).	[8]

2 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 KICSTOR complex protein ITFG2 (ITFG2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of KICSTOR complex protein ITFG2 (ITFG2).	[7]

References

• [1] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [6] 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.
• [7] 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.
• [8] 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.