Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3WBVYB)

DOT Name	GDNF family receptor alpha-1 (GFRA1)
Synonyms	GDNF receptor alpha-1; GDNFR-alpha-1; GFR-alpha-1; RET ligand 1; TGF-beta-related neurotrophic factor receptor 1
Gene Name	GFRA1
Related Disease	Adult teratoma ( ) Advanced cancer ( ) Alzheimer disease ( ) B-cell neoplasm ( ) Bone osteosarcoma ( ) Brain neoplasm ( ) Breast carcinoma ( ) Estrogen-receptor positive breast cancer ( ) Hepatitis C virus infection ( ) Hepatocellular carcinoma ( ) Hirschsprung disease ( ) Kennedy disease ( ) Medullary thyroid gland carcinoma ( ) Melanoma ( ) Motor neurone disease ( ) Neoplasm ( ) Neuralgia ( ) Osteosarcoma ( ) Pancreatic cancer ( ) Parkinsonian disorder ( ) Promyelocytic leukaemia ( ) Renal hypodysplasia/aplasia 4 ( ) Rheumatoid arthritis ( ) Schizophrenia ( ) Sciatic neuropathy ( ) Stroke ( ) Teratoma ( ) Thyroid tumor ( ) Triple negative breast cancer ( ) Vascular dementia ( ) Vesicoureteral reflux ( ) X-linked reticulate pigmentary disorder ( ) Amyotrophic lateral sclerosis ( ) Breast cancer ( ) Colorectal carcinoma ( ) Neuroendocrine neoplasm ( ) Breast fibrocystic disease ( ) Prostate cancer ( ) Prostate carcinoma ( ) Venous thromboembolism ( )
UniProt ID	GFRA1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	6Q2N
Pfam ID	PF02351
Sequence	MFLATLYFALPLLDLLLSAEVSGGDRLDCVKASDQCLKEQSCSTKYRTLRQCVAGKETNF SLASGLEAKDECRSAMEALKQKSLYNCRCKRGMKKEKNCLRIYWSMYQSLQGNDLLEDSP YEPVNSRLSDIFRVVPFISDVFQQVEHIPKGNNCLDAAKACNLDDICKKYRSAYITPCTT SVSNDVCNRRKCHKALRQFFDKVPAKHSYGMLFCSCRDIACTERRRQTIVPVCSYEEREK PNCLNLQDSCKTNYICRSRLADFFTNCQPESRSVSSCLKENYADCLLAYSGLIGTVMTPN YIDSSSLSVAPWCDCSNSGNDLEECLKFLNFFKDNTCLKNAIQAFGNGSDVTVWQPAFPV QTTTATTTTALRVKNKPLGPAGSENEIPTHVLPPCANLQAQKLKSNVSGNTHLCISNGNY EKEGLGASSHITTKSMAAPPSCGLSPLLVLVVTALSTLLSLTETS
Function	Receptor for GDNF. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor.
Reactome Pathway	RAF/MAP kinase cascade (R-HSA-5673001 ) RET signaling (R-HSA-8853659 ) NCAM1 interactions (R-HSA-419037 )

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Adult teratoma	DISBY81U	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[9]
Hirschsprung disease	DISUUSM1	Strong	Biomarker	[10]
Kennedy disease	DISXZVM1	Strong	Altered Expression	[11]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Genetic Variation	[12]
Melanoma	DIS1RRCY	Strong	Biomarker	[13]
Motor neurone disease	DISUHWUI	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Neuralgia	DISWO58J	Strong	Biomarker	[14]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	Strong	Biomarker	[15]
Parkinsonian disorder	DISHGY45	Strong	Biomarker	[16]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[17]
Renal hypodysplasia/aplasia 4	DISC7J0Y	Strong	Autosomal recessive	[18]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[19]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[20]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[21]
Stroke	DISX6UHX	Strong	Genetic Variation	[22]
Teratoma	DIS6ICY4	Strong	Genetic Variation	[1]
Thyroid tumor	DISLVKMD	Strong	Genetic Variation	[23]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[24]
Vascular dementia	DISVO82H	Strong	Biomarker	[25]
Vesicoureteral reflux	DISUL6SA	Strong	Biomarker	[26]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Biomarker	[27]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Altered Expression	[28]
Breast cancer	DIS7DPX1	moderate	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[29]
Neuroendocrine neoplasm	DISNPLOO	moderate	Genetic Variation	[30]
Breast fibrocystic disease	DISUM7ID	Limited	Altered Expression	[31]
Prostate cancer	DISF190Y	Limited	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[2]
Venous thromboembolism	DISUR7CR	Limited	Genetic Variation	[32]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[35]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[36]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of GDNF family receptor alpha-1 (GFRA1).	[38]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[39]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of GDNF family receptor alpha-1 (GFRA1).	[40]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of GDNF family receptor alpha-1 (GFRA1).	[41]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[38]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of GDNF family receptor alpha-1 (GFRA1).	[42]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GDNF family receptor alpha-1 (GFRA1).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of GDNF family receptor alpha-1 (GFRA1).	[44]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of GDNF family receptor alpha-1 (GFRA1).	[45]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of GDNF family receptor alpha-1 (GFRA1).	[46]
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⏷ Show the Full List of 15 Drug(s)

2 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 GDNF family receptor alpha-1 (GFRA1).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of GDNF family receptor alpha-1 (GFRA1).	[43]
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References

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2	RET Signaling in Prostate Cancer.Clin Cancer Res. 2017 Aug 15;23(16):4885-4896. doi: 10.1158/1078-0432.CCR-17-0528. Epub 2017 May 10.
3	Deficiency of GDNF Receptor GFR1 in Alzheimer's Neurons Results in Neuronal Death.J Neurosci. 2014 Sep 24;34(39):13127-38. doi: 10.1523/JNEUROSCI.2582-13.2014.
4	Silymarin amplifies apoptosis in ectopic endometrial tissue in rats with endometriosis; implication on growth factor GDNF, ERK1/2 and Bcl-6b expression.Acta Histochem. 2018 Nov;120(8):757-767. doi: 10.1016/j.acthis.2018.08.003. Epub 2018 Sep 5.
5	GFRA1: A Novel Molecular Target for the Prevention of Osteosarcoma Chemoresistance.Int J Mol Sci. 2018 Apr 4;19(4):1078. doi: 10.3390/ijms19041078.
6	Mutation and deletion analysis of GFR alpha-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours.Br J Cancer. 1999 May;80(3-4):383-6. doi: 10.1038/sj.bjc.6690367.
7	Preclinical evaluation of a GFRA1 targeted antibody-drug conjugate in breast cancer.Oncotarget. 2018 May 1;9(33):22960-22975. doi: 10.18632/oncotarget.25160. eCollection 2018 May 1.
8	Reciprocal feedback regulation of ST3GAL1 and GFRA1 signaling in breast cancer cells.Cancer Lett. 2018 Oct 10;434:184-195. doi: 10.1016/j.canlet.2018.07.026. Epub 2018 Jul 21.
9	Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C.Hepatology. 2005 Oct;42(4):846-53. doi: 10.1002/hep.20860.
10	Familial chronic megacolon presenting in childhood or adulthood: Seeking the presumed gene association.Neurogastroenterol Motil. 2019 Apr;31(4):e13550. doi: 10.1111/nmo.13550. Epub 2019 Jan 20.
11	Expression of GDNF and GDNFR-alpha mRNAs in muscles of patients with motor neuron diseases.Neurochem Res. 1999 Jun;24(6):785-90. doi: 10.1023/a:1020739831778.
12	Over-representation of a germline variant in the gene encoding RET co-receptor GFRalpha-1 but not GFRalpha-2 or GFRalpha-3 in cases with sporadic medullary thyroid carcinoma.Oncogene. 2001 Apr 19;20(17):2161-70. doi: 10.1038/sj.onc.1204289.
13	c-RET molecule in malignant melanoma from oncogenic RET-carrying transgenic mice and human cell lines.PLoS One. 2010 Apr 21;5(4):e10279. doi: 10.1371/journal.pone.0010279.
14	Pharmacological characterization and gene expression profiling of an L5/L6 spinal nerve ligation model for neuropathic pain in mice.Neuroscience. 2008 May 2;153(2):492-500. doi: 10.1016/j.neuroscience.2008.02.031. Epub 2008 Feb 29.
15	The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer.Carcinogenesis. 2014 Jan;35(1):103-13. doi: 10.1093/carcin/bgt312. Epub 2013 Sep 25.
16	Signaling of glial cell line-derived neurotrophic factor and its receptor GFR1 induce Nurr1 and Pitx3 to promote survival of grafted midbrain-derived neural stem cells in a rat model of Parkinson disease.J Neuropathol Exp Neurol. 2011 Sep;70(9):736-47. doi: 10.1097/NEN.0b013e31822830e5.
17	Reelin regulates male mouse reproductive capacity via the sertoli cells.J Cell Biochem. 2019 Feb;120(2):1174-1184. doi: 10.1002/jcb.26824. Epub 2018 Oct 18.
18	Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis. J Am Soc Nephrol. 2021 Jan;32(1):223-228. doi: 10.1681/ASN.2020040478. Epub 2020 Oct 5.
19	A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis.Arthritis Res Ther. 2016 Jan 18;18:12. doi: 10.1186/s13075-016-0920-6.
20	Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response.J Psychiatr Res. 2010 Aug;44(11):700-6. doi: 10.1016/j.jpsychires.2010.01.002. Epub 2010 Jan 29.
21	Sciatic nerve injury in adult rats causes distinct changes in the central projections of sensory neurons expressing different glial cell line-derived neurotrophic factor family receptors.J Comp Neurol. 2010 Aug 1;518(15):3024-45. doi: 10.1002/cne.22378.
22	Relative Telomere Length and Stroke Risk in a Chinese Han Population.J Mol Neurosci. 2018 Dec;66(4):475-481. doi: 10.1007/s12031-018-1160-9. Epub 2018 Oct 22.
23	Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer.Thyroid. 2002 Nov;12(11):1017-22. doi: 10.1089/105072502320908367.
24	circGFRA1 and GFRA1 act as ceRNAs in triple negative breast cancer by regulating miR-34a.J Exp Clin Cancer Res. 2017 Oct 16;36(1):145. doi: 10.1186/s13046-017-0614-1.
25	Dl-3-n-Butylphthalide Reduces Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion Through GDNF/GFR1/Ret Signaling Preventing Hippocampal Neuron Apoptosis.Front Cell Neurosci. 2019 Aug 13;13:351. doi: 10.3389/fncel.2019.00351. eCollection 2019.
26	Mutational analysis of the GDNF/RET-GDNFR alpha signaling complex in a kindred with vesicoureteral reflux.Hum Genet. 1998 Apr;102(4):474-8. doi: 10.1007/s004390050724.
27	Neurotrophic factor receptors in epiretinal membranes after human diabetic retinopathy.Diabetes Care. 2002 Jun;25(6):1060-5. doi: 10.2337/diacare.25.6.1060.
28	Expression of GDNF receptor (RET and GDNFR-alpha) mRNAs in the spinal cord of patients with amyotrophic lateral sclerosis.Brain Res. 1999 Feb 27;820(1-2):77-85. doi: 10.1016/s0006-8993(98)01344-4.
29	Expression of trophic factors receptors during reinnervation after recurrent laryngeal nerve injury.Laryngoscope. 2019 Nov;129(11):2537-2542. doi: 10.1002/lary.27649. Epub 2019 Feb 27.
30	Mutation analysis of glial cell line-derived neurotrophic factor, a ligand for an RET/coreceptor complex, in multiple endocrine neoplasia type 2 and sporadic neuroendocrine tumors.J Clin Endocrinol Metab. 1997 Sep;82(9):3025-8. doi: 10.1210/jcem.82.9.4197.
31	Prognostic significance of the expression of GFR1, GFR3 and syndecan-3, proteins binding ARTEMIN, in mammary carcinoma.BMC Cancer. 2013 Jan 26;13:34. doi: 10.1186/1471-2407-13-34.
32	Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism.J Thromb Haemost. 2011 Jun;9(6):1133-42. doi: 10.1111/j.1538-7836.2011.04272.x.
33	A comparative transcriptomic study on the effects of valproic acid on two different hESCs lines in a neural teratogenicity test system. Toxicol Lett. 2014 Nov 18;231(1):38-44.
34	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.
35	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
36	Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
37	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.
38	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.
39	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
40	Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
41	Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
42	Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
43	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.
44	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.
45	Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
46	Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.