Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7EX8JJ)

• DOT Name: Folliculin-interacting protein 2 (FNIP2)
• Synonyms: FNIP1-like protein; O6-methylguanine-induced apoptosis 1 protein
• Gene Name: FNIP2
• Related Disease:
  Advanced cancer
  Renal cell carcinoma
  Birt-Hogg-Dube syndrome
  Clear cell renal carcinoma
  Hip dysplasia, Beukes type
  Kidney cancer
  Neoplasm
  Renal carcinoma
• UniProt ID: FNIP2_HUMAN
• PDB ID: 6NZD; 6ULG; 7LSW; 7LT6; 8DHB
• Pfam ID: PF14638 ; PF14637 ; PF14636
• Sequence:
  MAPTLLQKLFNKRGSSGSSAAASAQGRAPKEGPAFSWSCSEFDLNEIRLIVYQDCDRRGR
  QVLFDSKAVQKIEEVTAQKTEDVPIKISAKCCQGSSSVSSSSSSSISSHSSSGGSSHHAK
  EQLPKYQYTRPASDVNMLGEMMFGSVAMSYKGSTLKIHYIRSPPQLMISKVFSARMGSFC
  GSTNNLQDSFEYINQDPNLGKLNTNQNSLGPCRTGSNLAHSTPVDMPSRGQNEDRDSGIA
  RSASLSSLLITPFPSPSSSTSSSSSYQRRWLRSQTTSLENGIIPRRSTDETFSLAEETCS
  SNPAMVRRKKIAISIIFSLCEKEEAQRNFQDFFFSHFPLFESHMNRLKSAIEKAMISCRK
  IAESSLRVQFYVSRLMEALGEFRGTIWNLYSVPRIAEPVWLTMMSGTLEKNQLCQRFLKE
  FTLLIEQINKNQFFAALLTAVLTYHLAWVPTVMPVDHPPIKAFSEKRTSQSVNMLAKTHP
  YNPLWAQLGDLYGAIGSPVRLTRTVVVGKQKDLVQRILYVLTYFLRCSELQENQLTWSGN
  HGEGDQVLNGSKIITALEKGEVEESEYVVITVRNEPALVPPILPPTAAERHNPWPTGFPE
  CPEGTDSRDLGLKPDKEANRRPEQGSEACSAGCLGPASDASWKPQNAFCGDEKNKEAPQD
  GSSRLPSCEVLGAGMKMDQQAVCELLKVEMPTRLPDRSVAWPCPDRHLREKPSLEKVTFQ
  IGSFASPESDFESRMKKMEERVKACGPSLEASEAADVAQDPQVSRSPFKPGFQENVCCPQ
  NRLSEGDEGESDKGFAEDRGSRNDMAADIAGQLSHAADLGTASHGAGGTGGRRLEATRGL
  YVKAAEGPVLEPVAPRCVQRGPGLVAGANIPCGDDNKKANFRTEGDIPRNESSDSALGDS
  DDEACASAMLDLGHGGDRTGGSLEVELPLPRSQSISTQNVRNFGRSLLAGYCPTYMPDLV
  LHGTGSDEKLKQCLVADLVHTVHHPVLDEPIAEAVCIIADTDKWSVQVATSQRKVTDNMK
  LGQDVLVSSQVSSLLQSILQLYKLHLPADFCIMHLEDRLQEMYLKSKMLSEYLRGHTRVH
  VKELGVVLGIESNDLPLLTAIASTHSPYVAQILL
• Function: Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3. Required to promote FLCN recruitment to lysosomes and interaction with Rag GTPases, leading to activation of the non-canonical mTORC1 signaling. In low-amino acid conditions, component of the lysosomal folliculin complex (LFC) on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, thereby inactivating mTORC1 and promoting nuclear translocation of TFEB and TFE3. Upon amino acid restimulation, disassembly of the LFC complex liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent inactivation of TFEB and TFE3. Together with FLCN, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy. In addition to its role in mTORC1 signaling, also acts as a co-chaperone of HSP90AA1/Hsp90: inhibits the ATPase activity of HSP90AA1/Hsp90, leading to activate both kinase and non-kinase client proteins of HSP90AA1/Hsp90. Acts as a scaffold to load client protein FLCN onto HSP90AA1/Hsp90. Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. May play a role in the signal transduction pathway of apoptosis induced by O6-methylguanine-mispaired lesions.
• Tissue Specificity: Widely expressed with highest levels in muscle, nasal mucosa, salivary gland, uvula, fat, liver, heart, placenta and pancreas . Moderately expressed in the lung, small intestine, kidney and brain. Lower levels detected in renal cell carcinoma than in normal kidney tissue . Higher levels detected in oncocytoma tumors than in normal kidney. Higher levels detected in renal cell carcinoma tumors than in normal kidney tissue .
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Renal cell carcinoma	DISQZ2X8	Definitive	Biomarker	[1]
Birt-Hogg-Dube syndrome	DISIN5TD	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Hip dysplasia, Beukes type	DISSTSIF	Strong	Biomarker	[2]
Kidney cancer	DISBIPKM	moderate	Biomarker	[1]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Renal carcinoma	DISER9XT	moderate	Biomarker	[1]

16 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 Folliculin-interacting protein 2 (FNIP2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Folliculin-interacting protein 2 (FNIP2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Folliculin-interacting protein 2 (FNIP2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Folliculin-interacting protein 2 (FNIP2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Folliculin-interacting protein 2 (FNIP2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Folliculin-interacting protein 2 (FNIP2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Folliculin-interacting protein 2 (FNIP2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Folliculin-interacting protein 2 (FNIP2).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Folliculin-interacting protein 2 (FNIP2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Folliculin-interacting protein 2 (FNIP2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Folliculin-interacting protein 2 (FNIP2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Folliculin-interacting protein 2 (FNIP2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Folliculin-interacting protein 2 (FNIP2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Folliculin-interacting protein 2 (FNIP2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Folliculin-interacting protein 2 (FNIP2).	[19]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Folliculin-interacting protein 2 (FNIP2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Folliculin-interacting protein 2 (FNIP2).	[16]

References

• [1] Nutrient-induced FNIP degradation by SCF-TRCP regulates FLCN complex localization and promotes renal cancer progression.Oncotarget. 2017 Feb 7;8(6):9947-9960. doi: 10.18632/oncotarget.14221.
• [2] Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):E3706-15. doi: 10.1073/pnas.1607592113. Epub 2016 Jun 14.
• [3] Identification and characterization of a novel folliculin-interacting protein FNIP2.Gene. 2008 May 31;415(1-2):60-7. doi: 10.1016/j.gene.2008.02.022. Epub 2008 Mar 4.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] 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.
• [8] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [9] 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.
• [10] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.