Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQBDP2E)

• DOT Name: FYVE, RhoGEF and PH domain-containing protein 2 (FGD2)
• Synonyms: Zinc finger FYVE domain-containing protein 4
• Gene Name: FGD2
• Related Disease:
  Hypothyroidism
  Inflammatory bowel disease
  Hirschsprung disease
• UniProt ID: FGD2_HUMAN
• Pfam ID: PF01363 ; PF00169 ; PF00621
• Sequence:
  MKGASEEKLASVSNLVTVFENSRTPEAAPRGQRLEDVHHRPECRPPESPGPREKTNVGEA
  VGSEPRTVSRRYLNSLKNKLSSEAWRKSCQPVTLSGSGTQEPEKKIVQELLETEQAYVAR
  LHLLDQVFFQELLKTARSSKAFPEDVVRVIFSNISSIYQFHSQFFLPELQRRLDDWTANP
  RIGDVIQKLAPFLKMYSEYVKNFERAAELLATWTDKSPLFQEVLTRIQSSEASGSLTLQH
  HMLEPVQRIPRYELLLKEYIQKLPAQAPDQADAQKALDMIFSAAQHSNAAITEMERLQDL
  WEVYQRLGLEDDIVDPSNTLLREGPVLKISFRRNDPMERYLFLFNNMLLYCVPRVIQVGA
  QFQVRTRIDVAGMKVRELMDAEFPHSFLVSGKQRTLELQARSQEEMISWMQAFQAAIDQI
  EKRNETFKAAAQGPEGDIQEQELQSEELGLRAPQWVRDKMVTMCMRCQEPFNALTRRRHH
  CRACGYVVCARCSDYRAELKYDDNRPNRVCLHCYAFLTGNVLPEAKEDKRRGILEKGSSA
  TPDQSLMCSFLQLIGDKWGKSGPRGWCVIPRDDPLVLYVYAAPQDMRAHTSIPLLGYQVT
  VGPQGDPRVFQLQQSGQLYTFKAETEELKGRWVKAMERAASGWSPSWPNDGDLSD
• Function: Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Activates JNK1 via CDC42 but not RAC1. Binds to phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 5-monophosphate, phosphatidylinositol 4-monophosphate and phosphatidylinositol 3-monophosphate.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  CDC42 GTPase cycle (R-HSA-9013148)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[1]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[2]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of FYVE, RhoGEF and PH domain-containing protein 2 (FGD2).	[4]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of FYVE, RhoGEF and PH domain-containing protein 2 (FGD2).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of FYVE, RhoGEF and PH domain-containing protein 2 (FGD2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of FYVE, RhoGEF and PH domain-containing protein 2 (FGD2).	[6]

References

• [1] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [2] Alterations of pre-mRNA splicing in human inflammatory bowel disease.Eur J Cell Biol. 2011 Jun-Jul;90(6-7):603-11. doi: 10.1016/j.ejcb.2010.11.010. Epub 2011 Feb 15.
• [3] Sotos syndrome associated with Hirschsprung's disease: a new case and exome-sequencing analysis.Pediatr Res. 2017 Jul;82(1):87-92. doi: 10.1038/pr.2017.106. Epub 2017 May 3.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [6] 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.
• [7] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.