Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUY7BSV)

• DOT Name: Formin-2 (FMN2)
• Gene Name: FMN2
• Related Disease:
  Acute lymphocytic leukaemia
  Alopecia
  Alzheimer disease
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Colorectal carcinoma
  Dementia
  Intellectual disability
  Intellectual disability, autosomal recessive 47
  Neoplasm
  Papillary renal cell carcinoma
  Post-traumatic stress disorder
  Renal cell carcinoma
  Advanced cancer
  Isolated congenital microcephaly
  Autosomal recessive non-syndromic intellectual disability
  Acute myelogenous leukaemia
  Lymphoid leukemia
  Neurodevelopmental disorder
• UniProt ID: FMN2_HUMAN
• PDB ID: 2YLE; 3R7G
• Pfam ID: PF02181
• Sequence:
  MGNQDGKLKRSAGDALHEGGGGAEDALGPRDVEATKKGSGGKKALGKHGKGGGGGGGGGE
  SGKKKSKSDSRASVFSNLRIRKNLSKGKGAGGSREDVLDSQALQTGELDSAHSLLTKTPD
  LSLSADEAGLSDTECADPFEVTGPGGPGPAEARVGGRPIAEDVETAAGAQDGQRTSSGSD
  TDIYSFHSATEQEDLLSDIQQAIRLQQQQQQQLQLQLQQQQQQQQLQGAEEPAAPPTAVS
  PQPGAFLGLDRFLLGPSGGAGEAPGSPDTEQALSALSDLPESLAAEPREPQQPPSPGGLP
  VSEAPSLPAAQPAAKDSPSSTAFPFPEAGPGEEAAGAPVRGAGDTDEEGEEDAFEDAPRG
  SPGEEWAPEVGEDAPQRLGEEPEEEAQGPDAPAAASLPGSPAPSQRCFKPYPLITPCYIK
  TTTRQLSSPNHSPSQSPNQSPRIKRRPEPSLSRGSRTALASVAAPAKKHRADGGLAAGLS
  RSADWTEELGARTPRVGGSAHLLERGVASDSGGGVSPALAAKASGAPAAADGFQNVFTGR
  TLLEKLFSQQENGPPEEAEKFCSRIIAMGLLLPFSDCFREPCNQNAQTNAASFDQDQLYT
  WAAVSQPTHSLDYSEGQFPRRVPSMGPPSKPPDEEHRLEDAETESQSAVSETPQKRSDAV
  QKEVVDMKSEGQATVIQQLEQTIEDLRTKIAELERQYPALDTEVASGHQGLENGVTASGD
  VCLEALRLEEKEVRHHRILEAKSIQTSPTEEGGVLTLPPVDGLPGRPPCPPGAESGPQTK
  FCSEISLIVSPRRISVQLDSHQPTQSISQPPPPPSLLWSAGQGQPGSQPPHSISTEFQTS
  HEHSVSSAFKNSCNIPSPPPLPCTESSSSMPGLGMVPPPPPPLPGMTVPTLPSTAIPQPP
  PLQGTEMLPPPPPPLPGAGIPPPPPLPGAGILPLPPLPGAGIPPPPPLPGAAIPPPPPLP
  GAGIPLPPPLPGAGIPPPPPLPGAGIPPPPPLPGAGIPPPPPLPGAGIPPPPPLPGAGIP
  PPPPLPGAGIPPPPPLPGAGIPPPPPLPGAGIPPPPPLPGAGIPPPPPLPGAGIPPPPPL
  PGAGIPPPPPLPGAGIPPPPPLPGVGIPPPPPLPGAGIPPPPPLPGAGIPPPPPLPGAGI
  PPPPPLPRVGIPPPPPLPGAGIPPPPPLPGAGIPPPPPLPGVGIPPPPPLPGVGIPPPPP
  LPGAGIPPPPPLPGMGIPPAPAPPLPPPGTGIPPPPLLPVSGPPLLPQVGSSTLPTPQVC
  GFLPPPLPSGLFGLGMNQDKGSRKQPIEPCRPMKPLYWTRIQLHSKRDSSTSLIWEKIEE
  PSIDCHEFEELFSKTAVKERKKPISDTISKTKAKQVVKLLSNKRSQAVGILMSSLHLDMK
  DIQHAVVNLDNSVVDLETLQALYENRAQSDELEKIEKHGRSSKDKENAKSLDKPEQFLYE
  LSLIPNFSERVFCILFQSTFSESICSIRRKLELLQKLCETLKNGPGVMQVLGLVLAFGNY
  MNGGNKTRGQADGFGLDILPKLKDVKSSDNSRSLLSYIVSYYLRNFDEDAGKEQCLFPLP
  EPQDLFQASQMKFEDFQKDLRKLKKDLKACEVEAGKVYQVSSKEHMQPFKENMEQFIIQA
  KIDQEAEENSLTETHKCFLETTAYFFMKPKLGEKEVSPNAFFSIWHEFSSDFKDFWKKEN
  KLLLQERVKEAEEVCRQKKGKSLYKIKPRHDSGIKAKISMKT
• Function: Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization. Acts as an actin nucleation factor and promotes assembly of actin filaments together with SPIRE1 and SPIRE2. Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport. Required for asymmetric spindle positioning, asymmetric oocyte division and polar body extrusion during female germ cell meiosis. Plays a role in responses to DNA damage, cellular stress and hypoxia by protecting CDKN1A against degradation, and thereby plays a role in stress-induced cell cycle arrest. Also acts in the nucleus: together with SPIRE1 and SPIRE2, promotes assembly of nuclear actin filaments in response to DNA damage in order to facilitate movement of chromatin and repair factors after DNA damage. Protects cells against apoptosis by protecting CDKN1A against degradation.
• Tissue Specificity: Expressed almost exclusively in the developing and mature central nervous system.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[1]
Alopecia	DIS37HU4	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Dementia	DISXL1WY	Strong	Genetic Variation	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Intellectual disability, autosomal recessive 47	DISU0EBQ	Strong	Autosomal recessive	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[4]
Post-traumatic stress disorder	DISHL1EY	Strong	Biomarker	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[8]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[6]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[9]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[10]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
toxaphene	DM4R657	Investigative	Formin-2 (FMN2) affects the response to substance of toxaphene.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Formin-2 (FMN2).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Formin-2 (FMN2).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Formin-2 (FMN2).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Formin-2 (FMN2).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Formin-2 (FMN2).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Formin-2 (FMN2).	[18]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Formin-2 (FMN2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Formin-2 (FMN2).	[12]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Formin-2 (FMN2).	[22]

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 Formin-2 (FMN2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Formin-2 (FMN2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Formin-2 (FMN2).	[21]

References

• [1] MicroRNA-144 regulates cancer cell proliferation and cell-cycle transition in acute lymphoblastic leukemia through the interaction of FMN2.J Gene Med. 2017 Jun;19(6-7). doi: 10.1002/jgm.2898.
• [2] De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature.Eur J Med Genet. 2012 Feb;55(2):117-9. doi: 10.1016/j.ejmg.2011.11.004. Epub 2011 Dec 2.
• [3] Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia.EMBO J. 2017 Oct 2;36(19):2815-2828. doi: 10.15252/embj.201796821. Epub 2017 Aug 2.
• [4] Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma.Nat Genet. 2011 Dec 4;44(1):17-9. doi: 10.1038/ng.1014.
• [5] Involvement of methylation-associated silencing of formin 2 in colorectal carcinogenesis.World J Gastroenterol. 2018 Nov 28;24(44):5013-5024. doi: 10.3748/wjg.v24.i44.5013.
• [6] Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability. Am J Hum Genet. 2014 Dec 4;95(6):721-8. doi: 10.1016/j.ajhg.2014.10.016.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] FilaminA and Formin2 regulate skeletal, muscular, and intestinal formation through mesenchymal progenitor proliferation.PLoS One. 2017 Dec 14;12(12):e0189285. doi: 10.1371/journal.pone.0189285. eCollection 2017.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] Gene profiling of Graffi murine leukemia virus-induced lymphoid leukemias: identification of leukemia markers and Fmn2 as a potential oncogene.Blood. 2011 Feb 10;117(6):1899-910. doi: 10.1182/blood-2010-10-311001. Epub 2010 Dec 6.
• [11] Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction.BMC Med Genomics. 2018 May 25;11(1):50. doi: 10.1186/s12920-018-0362-x.
• [12] 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.
• [13] 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.
• [14] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [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] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [23] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.