Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSE0XIF)

• DOT Name: Tyrosine-protein kinase Fes/Fps (FES)
• Synonyms: EC 2.7.10.2; Feline sarcoma/Fujinami avian sarcoma oncogene homolog; Proto-oncogene c-Fes; Proto-oncogene c-Fps; p93c-fes
• Gene Name: FES
• UniProt ID: FES_HUMAN
• PDB ID: 1WQU; 2DCR; 3BKB; 3CBL; 3CD3; 4DYL; 4E93; 6JMF; 7T1K; 7T1L
• EC Number: 2.7.10.2
• Pfam ID: PF00611 ; PF07714 ; PF00017
• Sequence:
  MGFSSELCSPQGHGVLQQMQEAELRLLEGMRKWMAQRVKSDREYAGLLHHMSLQDSGGQS
  RAISPDSPISQSWAEITSQTEGLSRLLRQHAEDLNSGPLSKLSLLIRERQQLRKTYSEQW
  QQLQQELTKTHSQDIEKLKSQYRALARDSAQAKRKYQEASKDKDRDKAKDKYVRSLWKLF
  AHHNRYVLGVRAAQLHHQHHHQLLLPGLLRSLQDLHEEMACILKEILQEYLEISSLVQDE
  VVAIHREMAAAAARIQPEAEYQGFLRQYGSAPDVPPCVTFDESLLEEGEPLEPGELQLNE
  LTVESVQHTLTSVTDELAVATEMVFRRQEMVTQLQQELRNEEENTHPRERVQLLGKRQVL
  QEALQGLQVALCSQAKLQAQQELLQTKLEHLGPGEPPPVLLLQDDRHSTSSSEQEREGGR
  TPTLEILKSHISGIFRPKFSLPPPLQLIPEVQKPLHEQLWYHGAIPRAEVAELLVHSGDF
  LVRESQGKQEYVLSVLWDGLPRHFIIQSLDNLYRLEGEGFPSIPLLIDHLLSTQQPLTKK
  SGVVLHRAVPKDKWVLNHEDLVLGEQIGRGNFGEVFSGRLRADNTLVAVKSCRETLPPDL
  KAKFLQEARILKQYSHPNIVRLIGVCTQKQPIYIVMELVQGGDFLTFLRTEGARLRVKTL
  LQMVGDAAAGMEYLESKCCIHRDLAARNCLVTEKNVLKISDFGMSREEADGVYAASGGLR
  QVPVKWTAPEALNYGRYSSESDVWSFGILLWETFSLGASPYPNLSNQQTREFVEKGGRLP
  CPELCPDAVFRLMEQCWAYEPGQRPSFSTIYQELQSIRKRHR
• Function: Tyrosine-protein kinase that acts downstream of cell surface receptors and plays a role in the regulation of the actin cytoskeleton, microtubule assembly, cell attachment and cell spreading. Plays a role in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Acts down-stream of the activated FCER1 receptor and the mast/stem cell growth factor receptor KIT. Plays a role in the regulation of mast cell degranulation. Plays a role in the regulation of cell differentiation and promotes neurite outgrowth in response to NGF signaling. Plays a role in cell scattering and cell migration in response to HGF-induced activation of EZR. Phosphorylates BCR and down-regulates BCR kinase activity. Phosphorylates HCLS1/HS1, PECAM1, STAT3 and TRIM28.
• Tissue Specificity: Widely expressed. Detected in adult colon epithelium (at protein level) . Expressed in melanocytes (at protein level) .
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)
  SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion (R-HSA-399955)
  CRMPs in Sema3A signaling (R-HSA-399956)
  Signaling by SCF-KIT (R-HSA-1433557)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Tyrosine-protein kinase Fes/Fps (FES).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tyrosine-protein kinase Fes/Fps (FES).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Tyrosine-protein kinase Fes/Fps (FES).	[7]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tyrosine-protein kinase Fes/Fps (FES).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tyrosine-protein kinase Fes/Fps (FES).	[3]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tyrosine-protein kinase Fes/Fps (FES).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tyrosine-protein kinase Fes/Fps (FES).	[6]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Tyrosine-protein kinase Fes/Fps (FES).	[3]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] 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.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.