Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT75489W)

• DOT Name: Follistatin-related protein 3 (FSTL3)
• Synonyms: Follistatin-like protein 3; Follistatin-related gene protein
• Gene Name: FSTL3
• UniProt ID: FSTL3_HUMAN
• PDB ID: 2KCX; 3B4V; 3SEK
• Pfam ID: PF09289 ; PF21333 ; PF07648
• Sequence:
  MRPGAPGPLWPLPWGALAWAVGFVSSMGSGNPAPGGVCWLQQGQEATCSLVLQTDVTRAE
  CCASGNIDTAWSNLTHPGNKINLLGFLGLVHCLPCKDSCDGVECGPGKACRMLGGRPRCE
  CAPDCSGLPARLQVCGSDGATYRDECELRAARCRGHPDLSVMYRGRCRKSCEHVVCPRPQ
  SCVVDQTGSAHCVVCRAAPCPVPSSPGQELCGNNNVTYISSCHMRQATCFLGRSIGVRHA
  GSCAGTPEEPPGGESAEEEENFV
• Function: Isoform 1 or the secreted form is a binding and antagonizing protein for members of the TGF-beta family, such us activin, BMP2 and MSTN. Inhibits activin A-, activin B-, BMP2- and MSDT-induced cellular signaling; more effective on activin A than on activin B. Involved in bone formation; inhibits osteoclast differentiationc. Involved in hematopoiesis; involved in differentiation of hemopoietic progenitor cells, increases hematopoietic cell adhesion to fibronectin and seems to contribute to the adhesion of hematopoietic precursor cells to the bone marrow stroma. Isoform 2 or the nuclear form is probably involved in transcriptional regulation via interaction with MLLT10.
• Tissue Specificity: Expressed in a wide range of tissues.
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Antagonism of Activin by Follistatin (R-HSA-2473224)

Molecular Interaction Atlas (MIA) of This DOT

1 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 Follistatin-related protein 3 (FSTL3).	[1]

13 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 Follistatin-related protein 3 (FSTL3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Follistatin-related protein 3 (FSTL3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Follistatin-related protein 3 (FSTL3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Follistatin-related protein 3 (FSTL3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Follistatin-related protein 3 (FSTL3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Follistatin-related protein 3 (FSTL3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Follistatin-related protein 3 (FSTL3).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Follistatin-related protein 3 (FSTL3).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Follistatin-related protein 3 (FSTL3).	[10]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Follistatin-related protein 3 (FSTL3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Follistatin-related protein 3 (FSTL3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Follistatin-related protein 3 (FSTL3).	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Follistatin-related protein 3 (FSTL3).	[14]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Expression of copper-responsive genes in HepG2 cells. Mol Cell Biochem. 2005 Nov;279(1-2):141-7.
• [5] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.