Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT34CXNN)

DOT Name GDNF family receptor alpha-2 (GFRA2)
Synonyms GDNF receptor alpha-2; GDNFR-alpha-2; GFR-alpha-2; GDNF receptor beta; GDNFR-beta; Neurturin receptor alpha; NRTNR-alpha; NTNR-alpha; RET ligand 2; TGF-beta-related neurotrophic factor receptor 2
Gene Name GFRA2
Related Disease
Adenoma ( )
Frontotemporal dementia ( )
Neoplasm ( )
Neuralgia ( )
Parkinsonian disorder ( )
Tardive dyskinesia ( )
X-linked reticulate pigmentary disorder ( )
Bipolar disorder ( )
Colorectal carcinoma ( )
Hirschsprung disease ( )
Neuroblastoma ( )
Pancreatic cancer ( )
UniProt ID
GFRA2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5MR4; 5MR5; 6GL7; 6Q2O; 6Q2R
Pfam ID
PF02351
Sequence
MILANVFCLFFFLDETLRSLASPSSLQGPELHGWRPPVDCVRANELCAAESNCSSRYRTL
RQCLAGRDRNTMLANKECQAALEVLQESPLYDCRCKRGMKKELQCLQIYWSIHLGLTEGE
EFYEASPYEPVTSRLSDIFRLASIFSGTGADPVVSAKSNHCLDAAKACNLNDNCKKLRSS
YISICNREISPTERCNRRKCHKALRQFFDRVPSEYTYRMLFCSCQDQACAERRRQTILPS
CSYEDKEKPNCLDLRGVCRTDHLCRSRLADFHANCRASYQTVTSCPADNYQACLGSYAGM
IGFDMTPNYVDSSPTGIVVSPWCSCRGSGNMEEECEKFLRDFTENPCLRNAIQAFGNGTD
VNVSPKGPSFQATQAPRVEKTPSLPDDLSDSTSLGTSVITTCTSVQEQGLKANNSKELSM
CFTELTTNIIPGSNKVIKPNSGPSRARPSAALTVLSVLMLKLAL
Function
Receptor for neurturin. Mediates the NRTN-induced autophosphorylation and activation of the RET receptor. Also able to mediate GDNF signaling through the RET tyrosine kinase receptor.; [Isoform 2]: Participates in NRTN-induced 'Ser-727' phosphorylation of STAT3.
Tissue Specificity Isoform 1 is found in both brain and placenta.
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

12 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Adenoma DIS78ZEV Strong Altered Expression [1]
Frontotemporal dementia DISKYHXL Strong Genetic Variation [2]
Neoplasm DISZKGEW Strong Biomarker [3]
Neuralgia DISWO58J Strong Biomarker [4]
Parkinsonian disorder DISHGY45 Strong Biomarker [5]
Tardive dyskinesia DISKA5RC Strong Genetic Variation [6]
X-linked reticulate pigmentary disorder DIS0RB5A Strong Altered Expression [7]
Bipolar disorder DISAM7J2 moderate Genetic Variation [8]
Colorectal carcinoma DIS5PYL0 moderate Biomarker [9]
Hirschsprung disease DISUUSM1 moderate Genetic Variation [10]
Neuroblastoma DISVZBI4 Disputed Biomarker [3]
Pancreatic cancer DISJC981 Limited Biomarker [11]
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⏷ Show the Full List of 12 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
6 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-2 (GFRA2). [12]
Tretinoin DM49DUI Approved Tretinoin increases the expression of GDNF family receptor alpha-2 (GFRA2). [13]
Estradiol DMUNTE3 Approved Estradiol increases the expression of GDNF family receptor alpha-2 (GFRA2). [14]
Triclosan DMZUR4N Approved Triclosan increases the expression of GDNF family receptor alpha-2 (GFRA2). [15]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of GDNF family receptor alpha-2 (GFRA2). [16]
Resveratrol DM3RWXL Phase 3 Resveratrol decreases the expression of GDNF family receptor alpha-2 (GFRA2). [17]
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⏷ Show the Full List of 6 Drug(s)
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 decreases the methylation of GDNF family receptor alpha-2 (GFRA2). [18]
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References

1 Expression of the pituitary stem/progenitor marker GFR2 in human pituitary adenomas and normal pituitary.Pituitary. 2015 Feb;18(1):31-41. doi: 10.1007/s11102-014-0553-1.
2 Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.Lancet Neurol. 2018 Jun;17(6):548-558. doi: 10.1016/S1474-4422(18)30126-1. Epub 2018 Apr 30.
3 GDNF family receptor alpha 2 promotes neuroblastoma cell proliferation by interacting with PTEN.Biochem Biophys Res Commun. 2019 Mar 12;510(3):339-344. doi: 10.1016/j.bbrc.2018.12.169. Epub 2019 Feb 2.
4 A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.Eur J Pain. 2015 Mar;19(3):392-9. doi: 10.1002/ejp.560.
5 Regulation of c-Ret, GFRalpha1, and GFRalpha2 in the substantia nigra pars compacta in a rat model of Parkinson's disease.J Neurobiol. 2002 Sep 15;52(4):343-51. doi: 10.1002/neu.10082.
6 Glial cell line-derived neurotrophic factor receptor alpha 2 (GFRA2) gene is associated with tardive dyskinesia.Psychopharmacology (Berl). 2010 Jun;210(3):347-54. doi: 10.1007/s00213-010-1829-4. Epub 2010 Apr 6.
7 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.
8 Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.Lancet. 2016 Mar 12;387(10023):1085-1093. doi: 10.1016/S0140-6736(16)00143-4. Epub 2016 Jan 22.
9 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.
10 Cloning and characterization of the human GFRA2 locus and investigation of the gene in Hirschsprung disease.Hum Genet. 2001 May;108(5):409-15. doi: 10.1007/s004390100506.
11 GFR2 prompts cell growth and chemoresistance through down-regulating tumor suppressor gene PTEN via Mir-17-5p in pancreatic cancer.Cancer Lett. 2016 Oct 1;380(2):434-441. doi: 10.1016/j.canlet.2016.06.016. Epub 2016 Jul 8.
12 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.
13 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
14 Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
15 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
16 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.
17 Effects of resveratrol on gene expression in renal cell carcinoma. Cancer Biol Ther. 2004 Sep;3(9):882-8. doi: 10.4161/cbt.3.9.1056. Epub 2004 Sep 21.
18 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.