Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKXLIJ6)

• DOT Name: F-BAR and double SH3 domains protein 2 (FCHSD2)
• Synonyms: Carom; Protein nervous wreck 1; NWK1; SH3 multiple domains protein 3
• Gene Name: FCHSD2
• Related Disease:
  Acute myelogenous leukaemia
  leukaemia
  Leukemia
  Advanced cancer
  Crohn disease
  Inflammatory bowel disease
  Juvenile idiopathic arthritis
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Systemic lupus erythematosus
  Endometrial carcinoma
• UniProt ID: FCSD2_HUMAN
• PDB ID: 2DL5; 2DL7; 6GBU
• Pfam ID: PF00611 ; PF00018 ; PF14604
• Sequence:
  MQPPPRKVKVTQELKNIQVEQMTKLQAKHQAECDLLEDMRTFSQKKAAIEREYAQGMQKL
  ASQYLKRDWPGVKADDRNDYRSMYPVWKSFLEGTMQVAQSRMNICENYKNFISEPARTVR
  SLKEQQLKRCVDQLTKIQTELQETVKDLAKGKKKYFETEQMAHAVREKADIEAKSKLSLF
  QSRISLQKASVKLKARRSECNSKATHARNDYLLTLAAANAHQDRYYQTDLVNIMKALDGN
  VYDHLKDYLIAFSRTELETCQAVQNTFQFLLENSSKVVRDYNLQLFLQENAVFHKPQPFQ
  FQPCDSDTSRQLESETGTTEEHSLNKEARKWATRVAREHKNIVHQQRVLNDLECHGAAVS
  EQSRAELEQKIDEARENIRKAEIIKLKAEARLDLLKQIGVSVDTWLKSAMNQVMEELENE
  RWARPPAVTSNGTLHSLNADTEREEGEEFEDNMDVFDDSSSSPSGTLRNYPLTCKVVYSY
  KASQPDELTIEEHEVLEVIEDGDMEDWVKARNKVGQVGYVPEKYLQFPTSNSLLSMLQSL
  AALDSRSHTSSNSTEAELVSGSLNGDASVCFVKALYDYEGQTDDELSFPEGAIIRILNKE
  NQDDDGFWEGEFNGRIGVFPSVLVEELSASENGDTPWMREIQISPSPKPHASLPPLPLYD
  QPPSSPYPSPDKRSSLYFPRSPSANEKSLHAESPGFSQASRHTPETSYGKLRPVRAAPPP
  PTQNHRRPAEKIEDVEITLV
• Function: Adapter protein that plays a role in endocytosis via clathrin-coated pits. Contributes to the internalization of cell surface receptors, such as integrin ITGB1 and transferrin receptor. Promotes endocytosis of EGFR in cancer cells, and thereby contributes to the down-regulation of EGFR signaling. Recruited to clathrin-coated pits during a mid-to-late stage of assembly, where it is required for normal progress from U-shaped intermediate stage pits to terminal, omega-shaped pits. Binds to membranes enriched in phosphatidylinositol 3,4-bisphosphate or phosphatidylinositol 3,4,5-trisphosphate. When bound to membranes, promotes actin polymerization via its interaction with WAS and/or WASL which leads to the activation of the Arp2/3 complex. Does not promote actin polymerisation in the absence of membranes.
• Tissue Specificity: Liver, brain, heart, placenta, skeletal muscle, pancreas, lung and kidney.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
leukaemia	DISS7D1V	Definitive	Altered Expression	[1]
Leukemia	DISNAKFL	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[3]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[4]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[2]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[7]
Endometrial carcinoma	DISXR5CY	Limited	Genetic Variation	[8]

13 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 F-BAR and double SH3 domains protein 2 (FCHSD2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of F-BAR and double SH3 domains protein 2 (FCHSD2).	[24]

3 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 F-BAR and double SH3 domains protein 2 (FCHSD2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of F-BAR and double SH3 domains protein 2 (FCHSD2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of F-BAR and double SH3 domains protein 2 (FCHSD2).	[21]

References

• [1] FCHSD2 predicts response to chemotherapy in acute myeloid leukemia patients.Leuk Res. 2012 Nov;36(11):1339-46. doi: 10.1016/j.leukres.2012.06.011. Epub 2012 Aug 16.
• [2] Role for ERK1/2-dependent activation of FCHSD2 in cancer cell-selective regulation of clathrin-mediated endocytosis.Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9570-E9579. doi: 10.1073/pnas.1810209115. Epub 2018 Sep 24.
• [3] Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations.Gut. 2014 Jan;63(1):80-7. doi: 10.1136/gutjnl-2013-305193. Epub 2013 Jul 14.
• [4] Genetic characteristics of inflammatory bowel disease in a Japanese population.J Gastroenterol. 2016 Jul;51(7):672-81. doi: 10.1007/s00535-015-1135-3. Epub 2015 Oct 28.
• [5] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [6] Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.Nat Genet. 2012 Sep;44(9):981-90. doi: 10.1038/ng.2383. Epub 2012 Aug 12.
• [7] Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.Arthritis Rheumatol. 2016 May;68(5):1197-1209. doi: 10.1002/art.39548.
• [8] Identification of nine new susceptibility loci for endometrial cancer.Nat Commun. 2018 Aug 9;9(1):3166. doi: 10.1038/s41467-018-05427-7.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [16] 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.
• [17] 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.
• [18] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.