Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT70IFEZ)

DOT Name Prokineticin-2 (PROK2)
Synonyms PK2; Protein Bv8 homolog
Gene Name PROK2
Related Disease
Hypogonadotropic hypogonadism 4 with or without anosmia ( )
Advanced cancer ( )
Alzheimer disease ( )
Autoimmune disease ( )
Bipolar disorder ( )
Breast cancer ( )
Breast carcinoma ( )
Congenital hypogonadotropic hypogonadism ( )
Glioma ( )
Graves disease ( )
Hyperglycemia ( )
Hypogonadism ( )
Hypogonadotropic hypogonadism 7 with or without anosmia ( )
Hypospadias ( )
Inflammatory bowel disease ( )
Irritable bowel syndrome ( )
Isolated congenital anosmia ( )
Klinefelter syndrome ( )
Major depressive disorder ( )
Methamphetamine dependence ( )
Mood disorder ( )
Neoplasm ( )
Neuralgia ( )
Non-insulin dependent diabetes ( )
Obesity ( )
Panhypopituitarism ( )
Psoriasis ( )
Sleep disorder ( )
Thyroid gland papillary carcinoma ( )
Trichohepatoenteric syndrome ( )
Colorectal carcinoma ( )
Hypogonadotropic hypogonadism ( )
Kallmann syndrome ( )
Hypopituitarism ( )
Parkinson disease ( )
Septooptic dysplasia ( )
UniProt ID
PROK2_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
Pfam ID
PF06607
Sequence
MRSLCCAPLLLLLLLPPLLLTPRAGDAAVITGACDKDSQCGGGMCCAVSIWVKSIRICTP
MGKLGDSCHPLTRKNNFGNGRQERRKRKRSKRKKEVPFFGRRMHHTCPCLPGLACLRTSF
NRFICLAQK
Function
May function as an output molecule from the suprachiasmatic nucleus (SCN) that transmits behavioral circadian rhythm. May also function locally within the SCN to synchronize output. Potently contracts gastrointestinal (GI) smooth muscle.
Tissue Specificity Expressed in the testis and, at low levels, in the small intestine.
Reactome Pathway
G alpha (q) signalling events (R-HSA-416476 )
Peptide ligand-binding receptors (R-HSA-375276 )

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Hypogonadotropic hypogonadism 4 with or without anosmia DISTMPHX Definitive Semidominant [1]
Advanced cancer DISAT1Z9 Strong Biomarker [2]
Alzheimer disease DISF8S70 Strong Biomarker [3]
Autoimmune disease DISORMTM Strong Biomarker [4]
Bipolar disorder DISAM7J2 Strong Biomarker [5]
Breast cancer DIS7DPX1 Strong Biomarker [6]
Breast carcinoma DIS2UE88 Strong Biomarker [6]
Congenital hypogonadotropic hypogonadism DISEV092 Strong Genetic Variation [7]
Glioma DIS5RPEH Strong Biomarker [8]
Graves disease DISU4KOQ Strong Biomarker [9]
Hyperglycemia DIS0BZB5 Strong Genetic Variation [10]
Hypogonadism DISICMNI Strong Genetic Variation [11]
Hypogonadotropic hypogonadism 7 with or without anosmia DISPBWEU Strong Biomarker [12]
Hypospadias DIS48CCP Strong Biomarker [13]
Inflammatory bowel disease DISGN23E Strong Biomarker [14]
Irritable bowel syndrome DIS27206 Strong Biomarker [14]
Isolated congenital anosmia DISP2NP8 Strong Genetic Variation [15]
Klinefelter syndrome DISOUI7W Strong Genetic Variation [16]
Major depressive disorder DIS4CL3X Strong Biomarker [17]
Methamphetamine dependence DIS1UU1B Strong Biomarker [17]
Mood disorder DISLVMWO Strong Biomarker [5]
Neoplasm DISZKGEW Strong Biomarker [4]
Neuralgia DISWO58J Strong Biomarker [4]
Non-insulin dependent diabetes DISK1O5Z Strong Biomarker [10]
Obesity DIS47Y1K Strong Biomarker [10]
Panhypopituitarism DISAKJ4T Strong Genetic Variation [18]
Psoriasis DIS59VMN Strong Biomarker [19]
Sleep disorder DIS3JP1U Strong Biomarker [16]
Thyroid gland papillary carcinoma DIS48YMM Strong Biomarker [9]
Trichohepatoenteric syndrome DISL3ODF Strong Genetic Variation [20]
Colorectal carcinoma DIS5PYL0 moderate Altered Expression [2]
Hypogonadotropic hypogonadism DIS8JSKR Supportive Autosomal dominant [21]
Kallmann syndrome DISO3HDG Supportive Autosomal dominant [22]
Hypopituitarism DIS1QT3G Limited Genetic Variation [23]
Parkinson disease DISQVHKL Limited Biomarker [24]
Septooptic dysplasia DISXYR1H Limited Genetic Variation [23]
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⏷ Show the Full List of 36 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 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 Prokineticin-2 (PROK2). [25]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Prokineticin-2 (PROK2). [31]
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8 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin increases the expression of Prokineticin-2 (PROK2). [26]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Prokineticin-2 (PROK2). [27]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of Prokineticin-2 (PROK2). [28]
Panobinostat DM58WKG Approved Panobinostat decreases the expression of Prokineticin-2 (PROK2). [28]
Ethanol DMDRQZU Approved Ethanol increases the expression of Prokineticin-2 (PROK2). [29]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Prokineticin-2 (PROK2). [30]
Bisphenol A DM2ZLD7 Investigative Bisphenol A affects the expression of Prokineticin-2 (PROK2). [29]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Prokineticin-2 (PROK2). [32]
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⏷ Show the Full List of 8 Drug(s)

References

1 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
2 Prokineticin 2 expression as a novel prognostic biomarker for human colorectal cancer.Oncotarget. 2018 Jul 10;9(53):30079-30091. doi: 10.18632/oncotarget.25706. eCollection 2018 Jul 10.
3 Involvement of the Chemokine Prokineticin-2 (PROK2) in Alzheimer's Disease: From Animal Models to the Human Pathology.Cells. 2019 Nov 13;8(11):1430. doi: 10.3390/cells8111430.
4 The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis.Physiol Rev. 2018 Apr 1;98(2):1055-1082. doi: 10.1152/physrev.00012.2017.
5 PROKR2 is associated with methamphetamine dependence in the Japanese population. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):1033-6. doi: 10.1016/j.pnpbp.2010.05.018. Epub 2010 May 24.
6 Involvement of Prokineticin 2-expressing Neutrophil Infiltration in 5-Fluorouracil-induced Aggravation of Breast Cancer Metastasis to Lung.Mol Cancer Ther. 2018 Jul;17(7):1515-1525. doi: 10.1158/1535-7163.MCT-17-0845. Epub 2018 Apr 11.
7 Triallelic digenic mutation in the prokineticin 2 and GNRH receptor genes in two brothers with normosmic congenital hypogonadotropic hypogonadism.Endocr Res. 2015;40(3):166-71. doi: 10.3109/07435800.2014.982327. Epub 2014 Dec 22.
8 MicroRNA-374a Governs Aggressive Cell Behaviors of Glioma by Targeting Prokineticin 2.Technol Cancer Res Treat. 2019 Jan 1;18:1533033818821401. doi: 10.1177/1533033818821401.
9 Upregulation of endocrine gland-derived vascular endothelial growth factor in papillary thyroid cancers displaying infiltrative patterns, lymph node metastases, and BRAF mutation.Thyroid. 2011 Apr;21(4):391-9. doi: 10.1089/thy.2010.0168.
10 New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans.Mol Metab. 2019 Nov;29:182-196. doi: 10.1016/j.molmet.2019.08.016. Epub 2019 Aug 28.
11 Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.J Clin Endocrinol Metab. 2008 Sep;93(9):3551-9. doi: 10.1210/jc.2007-2654. Epub 2008 Jun 17.
12 Prokineticins and their G protein-coupled receptors in health and disease.Prog Mol Biol Transl Sci. 2019;161:149-179. doi: 10.1016/bs.pmbts.2018.09.006. Epub 2018 Oct 24.
13 Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46,XY under-virilised boys.Hum Genomics. 2017 Feb 16;11(1):1. doi: 10.1186/s40246-017-0098-2.
14 Increased prokineticin 2 expression in gut inflammation: role in visceral pain and intestinal ion transport.Neurogastroenterol Motil. 2012 Jan;24(1):65-75, e12. doi: 10.1111/j.1365-2982.2011.01804.x. Epub 2011 Nov 3.
15 PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency.Eur J Endocrinol. 2012 Dec 10;168(1):31-7. doi: 10.1530/EJE-12-0578. Print 2013 Jan.
16 Kallmann syndrome caused by mutations in the PROK2 and PROKR2 genes: pathophysiology and genotype-phenotype correlations.Front Horm Res. 2010;39:121-132. doi: 10.1159/000312698. Epub 2010 Apr 8.
17 Lack of association between translin-associated factor X gene (TSNAX) and methamphetamine dependence in the Japanese population.Prog Neuropsychopharmacol Biol Psychiatry. 2011 Aug 15;35(7):1618-22. doi: 10.1016/j.pnpbp.2011.06.001. Epub 2011 Jun 13.
18 Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab. 2012 Apr;97(4):E694-9. doi: 10.1210/jc.2011-2938. Epub 2012 Feb 8.
19 Prokineticin 2 Plays a Pivotal Role in Psoriasis.EBioMedicine. 2016 Nov;13:248-261. doi: 10.1016/j.ebiom.2016.10.022. Epub 2016 Oct 19.
20 The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism.Nat Rev Endocrinol. 2009 Oct;5(10):569-76. doi: 10.1038/nrendo.2009.177. Epub 2009 Aug 25.
21 Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17447-52. doi: 10.1073/pnas.0707173104. Epub 2007 Oct 24.
22 Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab. 2008 Oct;93(10):4113-8. doi: 10.1210/jc.2008-0958. Epub 2008 Aug 5.
23 Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia.J Clin Endocrinol Metab. 2013 Mar;98(3):E547-57. doi: 10.1210/jc.2012-3067. Epub 2013 Feb 5.
24 Prokineticin-2 upregulation during neuronal injury mediates a compensatory protective response against dopaminergic neuronal degeneration.Nat Commun. 2016 Oct 5;7:12932. doi: 10.1038/ncomms12932.
25 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.
26 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
27 Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
28 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.
29 Bisphenol A alters transcript levels of biomarker genes for Major Depressive Disorder in vascular endothelial cells and colon cancer cells. Chemosphere. 2016 Jun;153:75-7. doi: 10.1016/j.chemosphere.2015.12.085. Epub 2016 Mar 21.
30 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
31 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.
32 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.