Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKJS2BZ)

• DOT Name: Intraflagellar transport protein 20 homolog (IFT20)
• Synonyms: hIFT20
• Gene Name: IFT20
• Related Disease:
  Ciliopathy
  Neoplasm
  Odontochondrodysplasia
  Achondroplasia
  Advanced cancer
  Colorectal carcinoma
• UniProt ID: IFT20_HUMAN
• Pfam ID: PF14931
• Sequence:
  MAKDILGEAGLHFDELNKLRVLDPEVTQQTIELKEECKDFVDKIGQFQKIVGGLIELVDQ
  LAKEAENEKMKAIGARNLLKSIAKQREAQQQQLQALIAEKKMQLERYRVEYEALCKVEAE
  QNEFIDQFIFQK
• Function: Part of intraflagellar transport (IFT) particles involved in ciliary process assembly. May play a role in the trafficking of ciliary membrane proteins from the Golgi complex to the cilium. Regulates the platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway. Required for protein stability of E3 ubiquitin ligases CBL and CBLB that mediate ubiquitination and internalization of PDGFRA for proper feedback inhibition of PDGFRA signaling. Essential for male fertility. Plays an important role in spermatogenesis, particularly spermiogenesis, when germ cells form flagella. May play a role in the transport of flagellar proteins ODF2 and SPAG16 to build sperm flagella and in the removal of redundant sperm cytoplasm. Also involved in autophagy since it is required for trafficking of ATG16L and the expansion of the autophagic compartment.
• Tissue Specificity: Expressed in almost all tissues.
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Odontochondrodysplasia	DIS7OXG7	Strong	Biomarker	[3]
Achondroplasia	DISYWN2O	moderate	Biomarker	[4]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Intraflagellar transport protein 20 homolog (IFT20).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Intraflagellar transport protein 20 homolog (IFT20).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Intraflagellar transport protein 20 homolog (IFT20).	[15]

References

• [1] A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi.Nat Commun. 2016 Nov 24;7:13586. doi: 10.1038/ncomms13586.
• [2] Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness.Sci Rep. 2017 Jan 26;7(1):1. doi: 10.1038/s41598-016-0028-x.
• [3] Hypomorphic mutations of TRIP11 cause odontochondrodysplasia.JCI Insight. 2019 Feb 7;4(3):e124701. doi: 10.1172/jci.insight.124701.
• [4] Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia.Hum Mol Genet. 2018 Jan 1;27(1):1-13. doi: 10.1093/hmg/ddx374.
• [5] Intraflagellar transport 20 promotes collective cancer cell invasion by regulating polarized organization of Golgi-associated microtubules.Cancer Sci. 2019 Apr;110(4):1306-1316. doi: 10.1111/cas.13970. Epub 2019 Feb 28.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.