Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB1CC41)

• DOT Name: Folliculin-interacting protein 1 (FNIP1)
• Gene Name: FNIP1
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Birt-Hogg-Dube syndrome
  Cardiomyopathy
  Clear cell renal carcinoma
  FNIP1-associated syndrome
  Immunodeficiency 93 and hypertrophic cardiomyopathy
  Kidney cancer
  Kidney neoplasm
  Renal carcinoma
  Episodic kinesigenic dyskinesia 1
  Neoplasm
  Polycystic kidney disease
  Renal cell carcinoma
• UniProt ID: FNIP1_HUMAN
• Pfam ID: PF14638 ; PF14637 ; PF14636
• Sequence:
  MAPTLFQKLFSKRTGLGAPGRDARDPDCGFSWPLPEFDPSQIRLIVYQDCERRGRNVLFD
  SSVKRRNEDISVSKLGSDAQVKVFGKCCQLKPGGDSSSSLDSSVTSSSDIKDQCLKYQGS
  RCSSDANMLGEMMFGSVAMSYKGSTLKIHQIRSPPQLMLSKVFTARTGSSICGSLNTLQD
  SLEFINQDNNTLKADNNTVINGLLGNIGLSQFCSPRRAFSEQGPLRLIRSASFFAVHSNP
  MDMPGRELNEDRDSGIARSASLSSLLITPFPSPNSSLTRSCASSYQRRWRRSQTTSLENG
  VFPRWSIEESFNLSDESCGPNPGIVRKKKIAIGVIFSLSKDEDENNKFNEFFFSHFPLFE
  SHMNKLKSAIEQAMKMSRRSADASQRSLAYNRIVDALNEFRTTICNLYTMPRIGEPVWLT
  MMSGTPEKNHLCYRFMKEFTFLMENASKNQFLPALITAVLTNHLAWVPTVMPNGQPPIKI
  FLEKHSSQSVDMLAKTHPYNPLWAQLGDLYGAIGSPVRLARTVVVGKRQDMVQRLLYFLT
  YFIRCSELQETHLLENGEDEAIVMPGTVITTTLEKGEIEESEYVLVTMHRNKSSLLFKES
  EEIRTPNCNCKYCSHPLLGQNVENISQQEREDIQNSSKELLGISDECQMISPSDCQEENA
  VDVKQYRDKLRTCFDAKLETVVCTGSVPVDKCALSESGLESTEETWQSEKLLDSDSHTGK
  AMRSTGMVVEKKPPDKIVPASFSCEAAQTKVTFLIGDSMSPDSDTELRSQAVVDQITRHH
  TKPLKEERGAIDQHQETKQTTKDQSGESDTQNMVSEEPCELPCWNHSDPESMSLFDEYFN
  DDSIETRTIDDVPFKTSTDSKDHCCMLEFSKILCTKNNKQNNEFCKCIETVPQDSCKTCF
  PQQDQRDTLSILVPHGDKESSDKKIAVGTEWDIPRNESSDSALGDSESEDTGHDMTRQVS
  SYYGGEQEDWAEEDEIPFPGSKLIEVSAVQPNIANFGRSLLGGYCSSYVPDFVLQGIGSD
  ERFRQCLMSDLSHAVQHPVLDEPIAEAVCIIADMDKWTVQVASSQRRVTDNKLGKEVLVS
  SLVSNLLHSTLQLYKHNLSPNFCVMHLEDRLQELYFKSKMLSEYLRGQMRVHVKELGVVL
  GIESSDLPLLAAVASTHSPYVAQILL
• 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: following gradual phosphorylation by CK2, 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. Also acts as a core component of the reductive stress response by inhibiting activation of mitochondria in normal conditions: in response to reductive stress, the conserved Cys degron is reduced, leading to recognition and polyubiquitylation by the CRL2(FEM1B) complex, followed by proteasomal. Required for B-cell development.
• Tissue Specificity: Strong expression is found in the heart, liver placenta, muscle, nasal mucosa, salivary gland and uvula and moderate expression in kidney and lung. Higher levels detected in clear cell renal cell carcinoma (RCC) and chromophobe RCC than in normal kidney tissue. Expressed in peripheral blood mononuclear cells .
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Birt-Hogg-Dube syndrome	DISIN5TD	Strong	Biomarker	[3]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
FNIP1-associated syndrome	DISRZURH	Strong	Autosomal recessive	[6]
Immunodeficiency 93 and hypertrophic cardiomyopathy	DISYXTOW	Strong	Autosomal recessive	[4]
Kidney cancer	DISBIPKM	Strong	Biomarker	[7]
Kidney neoplasm	DISBNZTN	Strong	Genetic Variation	[8]
Renal carcinoma	DISER9XT	Strong	Biomarker	[7]
Episodic kinesigenic dyskinesia 1	DISGVQMP	moderate	Biomarker	[5]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Polycystic kidney disease	DISWS3UY	moderate	Biomarker	[5]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[5]

11 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 1 (FNIP1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Folliculin-interacting protein 1 (FNIP1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Folliculin-interacting protein 1 (FNIP1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Folliculin-interacting protein 1 (FNIP1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Folliculin-interacting protein 1 (FNIP1).	[11]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Folliculin-interacting protein 1 (FNIP1).	[13]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Folliculin-interacting protein 1 (FNIP1).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Folliculin-interacting protein 1 (FNIP1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Folliculin-interacting protein 1 (FNIP1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Folliculin-interacting protein 1 (FNIP1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Folliculin-interacting protein 1 (FNIP1).	[20]

3 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 increases the phosphorylation of Folliculin-interacting protein 1 (FNIP1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Folliculin-interacting protein 1 (FNIP1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Folliculin-interacting protein 1 (FNIP1).	[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] A novel Alzheimer disease locus located near the gene encoding tau protein.Mol Psychiatry. 2016 Jan;21(1):108-17. doi: 10.1038/mp.2015.23. Epub 2015 Mar 17.
• [3] The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dub syndrome is required for murine B-cell development.Blood. 2012 Aug 9;120(6):1254-61. doi: 10.1182/blood-2012-02-410407. Epub 2012 Jun 18.
• [4] 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.
• [5] Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation.PLoS One. 2018 Jun 13;13(6):e0197973. doi: 10.1371/journal.pone.0197973. eCollection 2018.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] Birt-Hogg-Dub syndrome: from gene discovery to molecularly targeted therapies.Fam Cancer. 2013 Sep;12(3):357-64. doi: 10.1007/s10689-012-9574-y.
• [8] 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.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] 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.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [14] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] 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.
• [19] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.