Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKD9XST)

• DOT Name: Interleukin-17 receptor D (IL17RD)
• Synonyms: IL-17 receptor D; IL-17RD; IL17Rhom; Interleukin-17 receptor-like protein; Sef homolog; hSef
• Gene Name: IL17RD
• Related Disease:
  Anemia
  Arthritis
  Rheumatoid arthritis
  Dermatitis
  Glioblastoma multiforme
  Glioma
  Nephritis
  Psoriasis
  Ulcerative colitis
  Kallmann syndrome
  Hypogonadotropic hypogonadism 18 with or without anosmia
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
• UniProt ID: I17RD_HUMAN
• Pfam ID: PF16742 ; PF08357
• Sequence:
  MAPWLQLCSVFFTVNACLNGSQLAVAAGGSGRARGADTCGWRGVGPASRNSGLYNITFKY
  DNCTTYLNPVGKHVIADAQNITISQYACHDQVAVTILWSPGALGIEFLKGFRVILEELKS
  EGRQCQQLILKDPKQLNSSFKRTGMESQPFLNMKFETDYFVKVVPFPSIKNESNYHPFFF
  RTRACDLLLQPDNLACKPFWKPRNLNISQHGSDMQVSFDHAPHNFGFRFFYLHYKLKHEG
  PFKRKTCKQEQTTETTSCLLQNVSPGDYIIELVDDTNTTRKVMHYALKPVHSPWAGPIRA
  VAITVPLVVISAFATLFTVMCRKKQQENIYSHLDEESSESSTYTAALPRERLRPRPKVFL
  CYSSKDGQNHMNVVQCFAYFLQDFCGCEVALDLWEDFSLCREGQREWVIQKIHESQFIIV
  VCSKGMKYFVDKKNYKHKGGGRGSGKGELFLVAVSAIAEKLRQAKQSSSAALSKFIAVYF
  DYSCEGDVPGILDLSTKYRLMDNLPQLCSHLHSRDHGLQEPGQHTRQGSRRNYFRSKSGR
  SLYVAICNMHQFIDEEPDWFEKQFVPFHPPPLRYREPVLEKFDSGLVLNDVMCKPGPESD
  FCLKVEAAVLGATGPADSQHESQHGGLDQDGEARPALDGSAALQPLLHTVKAGSPSDMPR
  DSGIYDSSVPSSELSLPLMEGLSTDQTETSSLTESVSSSSGLGEEEPPALPSKLLSSGSC
  KADLGCRSYTDELHAVAPL
• Function: Feedback inhibitor of fibroblast growth factor mediated Ras-MAPK signaling and ERK activation. Regulates the nuclear ERK signaling pathway by spatially blocking nuclear translocation of activated ERK without inhibiting cytoplasmic phosphorylation of ERK. Mediates JNK activation and may be involved in apoptosis. May inhibit FGF-induced FGFR1 tyrosine phosphorylation. Might have a role in the early stages of fate specification of GnRH-secreting neurons. Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells.
• Tissue Specificity: Expressed in umbilical vein endothelial cells and in several highly vascularized tissues such as kidney, colon, skeletal muscle, heart and small intestine. Highly expressed in ductal epithelial cells of salivary glands, seminal vesicles and the collecting tubules of the kidney. Isoform 1 is also highly expressed in both fetal and adult brain, pituitary, tonsils, spleen, adenoids, fetal kidney, liver, testes and ovary. Isoform 1 is also expressed at moderate levels in primary aortic endothelial cells and adrenal medulla, and at low levels in adrenal cortex. Isoform 4 is specifically and highly expressed in pituitary, fetal brain and umbilical vein endothelial cells.
• Reactome Pathway: MAP2K and MAPK activation (R-HSA-5674135)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Definitive	Genetic Variation	[1]
Arthritis	DIST1YEL	Definitive	Altered Expression	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[2]
Dermatitis	DISY5SZC	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Nephritis	DISQZQ70	Strong	Altered Expression	[6]
Psoriasis	DIS59VMN	Strong	Altered Expression	[3]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[7]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[8]
Hypogonadotropic hypogonadism 18 with or without anosmia	DISEWQ6V	Limited	Autosomal dominant	[8]
Prostate cancer	DISF190Y	Limited	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[9]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[10]

2 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 Interleukin-17 receptor D (IL17RD).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Interleukin-17 receptor D (IL17RD).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-17 receptor D (IL17RD).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Interleukin-17 receptor D (IL17RD).	[13]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Interleukin-17 receptor D (IL17RD).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Interleukin-17 receptor D (IL17RD).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Interleukin-17 receptor D (IL17RD).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Interleukin-17 receptor D (IL17RD).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Interleukin-17 receptor D (IL17RD).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interleukin-17 receptor D (IL17RD).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Interleukin-17 receptor D (IL17RD).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Interleukin-17 receptor D (IL17RD).	[20]

References

• [1] Association of cytokine and Toll-like receptor gene polymorphisms with severe malaria in three regions of Cameroon.PLoS One. 2013 Nov 27;8(11):e81071. doi: 10.1371/journal.pone.0081071. eCollection 2013.
• [2] The Impact of MicroRNA-223-3p on IL-17 Receptor D Expression in Synovial Cells.PLoS One. 2017 Jan 5;12(1):e0169702. doi: 10.1371/journal.pone.0169702. eCollection 2017.
• [3] Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation.Sci Immunol. 2019 Jun 7;4(36):eaau9657. doi: 10.1126/sciimmunol.aau9657.
• [4] Upregulated circular RNA circ_0074027 promotes glioblastoma cell growth and invasion by regulating miR-518a-5p/IL17RD signaling pathway.Biochem Biophys Res Commun. 2019 Mar 19;510(4):515-519. doi: 10.1016/j.bbrc.2019.01.140. Epub 2019 Feb 7.
• [5] Elevation of circ-PITX1 upregulates interleukin 17 receptor D expression via sponging miR-518a-5p and facilitates cell progression in glioma.J Cell Biochem. 2019 Oct;120(10):16495-16502. doi: 10.1002/jcb.28868. Epub 2019 May 8.
• [6] Tumor necrosis factor receptor 2 (TNFR2)interleukin-17 receptor D (IL-17RD) heteromerization reveals a novel mechanism for NF-B activation.J Biol Chem. 2015 Jan 9;290(2):861-71. doi: 10.1074/jbc.M114.586560. Epub 2014 Nov 5.
• [7] miR-193a-3p is a Key Tumor Suppressor in Ulcerative Colitis-Associated Colon Cancer and Promotes Carcinogenesis through Upregulation of IL17RD.Clin Cancer Res. 2017 Sep 1;23(17):5281-5291. doi: 10.1158/1078-0432.CCR-17-0171. Epub 2017 Jun 9.
• [8] Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008.
• [9] Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease.Br J Cancer. 2009 Dec 1;101(11):1891-9. doi: 10.1038/sj.bjc.6605379. Epub 2009 Nov 3.
• [10] Loss of Sef (similar expression to FGF) expression is associated with high grade and metastatic prostate cancer.Oncogene. 2006 Jul 6;25(29):4122-7. doi: 10.1038/sj.onc.1209428. Epub 2006 Feb 13.
• [11] 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.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] 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.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] 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.
• [20] 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.