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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 384 | 20p12.3 | PROKR2 | prokineticin receptor 2 | 24,46 |
| Mouse | 7 | 381 | 2 F2 | Prokr2 | prokineticin receptor 2 | 11 |
| Rat | 7 | 383 | 3q36 | Prokr2 | prokineticin receptor 2 | 27,33 |
| Previous and Unofficial Names |
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| GPR73b [24] | VEGFR-2 [23] | GPR73a [24] | GPRg2 [46] | I5E [27] | |
| Database Links |
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| Specialist databases | |
| GPCRdb | pkr2_human (Hs), pkr2_mouse (Mm), pkr2_rat (Rn) |
| Other databases | |
| Alphafold | Q8NFJ6 (Hs), Q8K458 (Mm), Q8R415 (Rn) |
| ChEMBL Target | CHEMBL5548 (Hs) |
| Ensembl Gene | ENSG00000101292 (Hs), ENSMUSG00000050558 (Mm), ENSRNOG00000021266 (Rn) |
| Entrez Gene | 128674 (Hs), 246313 (Mm), 192649 (Rn) |
| Human Protein Atlas | ENSG00000101292 (Hs) |
| KEGG Gene | hsa:128674 (Hs), mmu:246313 (Mm), rno:192649 (Rn) |
| OMIM | 607123 (Hs) |
| Orphanet | ORPHA118044 (Hs) |
| Pharos | Q8NFJ6 (Hs) |
| RefSeq Nucleotide | NM_144773 (Hs), NM_144944 (Mm), NM_138978 (Rn) |
| RefSeq Protein | NP_658986 (Hs), NP_659193 (Mm), NP_620434 (Rn) |
| UniProtKB | Q8NFJ6 (Hs), Q8K458 (Mm), Q8R415 (Rn) |
| Wikipedia | PROKR2 (Hs) |
| Associated Proteins |
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| Natural/Endogenous Ligands |
| prokineticin-2β {Sp: Human} |
| prokineticin-1 {Sp: Human} |
| prokineticin-2 {Sp: Human} |
| prokineticin-1 {Sp: Mouse} |
| prokineticin-2 {Sp: Mouse, Rat} |
| prokineticin-1 {Sp: Rat} |
| Comments: Prokineticin-2 is the higher potency endogenous agonist |
| Potency order of endogenous ligands (Human) |
| prokineticin-2 (PROK2, Q9HC23) > prokineticin-1 (PROK1, Q9HC23) > prokineticin-2β (PROK2, Q9HC23) [10,24,27,46] |
Download all structure-activity data for this target as a CSV file 
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| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gq/G11 family | Phospholipase C stimulation |
| Comments: Coexpression of Gqi5 with the PKR2 receptor increases the PK stimulated Ca2+ response in HEK 293 cells transfected with the human PKR2 receptor [10]. | |
| References: 10,30 | |
| Secondary Transduction Mechanisms |
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| Transducer | Effector/Response |
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Gs family Gi/Go family |
Adenylyl cyclase stimulation Other - See Comments |
| Comments: Pertussis toxin (PTX) inhibits PK1-induced mitogen-activated protein kinase signaling suggesting that PKR2 couples to Gi/Go proteins [25]. | |
| References: 10,25 | |
| Tissue Distribution
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| Expression Datasets |
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| Functional Assays
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| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| In zebrafish knock-down of the PKR2 orthologue provided a model that has been used to uncover the complex regulatory role that this receptor plays in the hypothalamus-pituitary-gonadal axis [4]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mutations found in the homozygous state: Kallmann syndrome (R85C, R85H, Y140X, R164Q, L173R, V274D, P290S, G234D, R268C). For other possible variants of PKR2 due to single nucleotide polymorphism (SNP) see reference [48] and the Exome Variant Server Data Browser. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||||||
| In most cases, only one allele is affected by the mutation. In heterozygotes the two main clinical features of Kallmann syndrome may be incomplete. Several phenotypes are possible for individuals harboring only one mutant allele: (1) no symptoms, with normal olfaction and complete pubertal development (2) congenital isolated (idiopathic) hypogonadotropic hypogonadism (IHH) but normal olfaction (3) anosmia/hyposmia but normal pubertal development and gonadal function (4) the two cardinal clinical Kallmann syndrome signs, anosmia and IHH. These phenotypic dissociations can be seen in family members with the same PROKR2 mutations. By contrast, patients with two mutant alleles almost always have the cardinal signs of Kallmann syndrome. Other mutations in PROKR2 associated with cancer [35] (*, stop codon; fs, frameshift) carcinoma: lung: D38N, R47W, K53N, K83N, D99N, W121*, I174N, A175S, P213H, E231D ovary: R85C, L95P, R298C, R353H breast: S23F, G293S, M341I liver L95P, I184fs*56 rectum C242*, R368I larynx D112Y, C279S pharynx R268G prostate Y220* kidney: G124C endometrium: V115M colon: A322T melanoma: E110K, R298C neuroblastoma: F109L glioma: M165I others: pancreas: A77T, V331M |
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2. Abreu AP, Trarbach EB, de Castro M, Frade Costa EM, Versiani B, Matias Baptista MT, Garmes HM, Mendonca BB, Latronico AC. (2008) Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab, 93 (10): 4113-8. [PMID:18682503]
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4. Bassi I, Luzzani F, Marelli F, Vezzoli V, Cotellessa L, Prober DA, Persani L, Gothilf Y, Bonomi M. (2020) Knocking-down of the Prokineticin receptor 2 affects reveals its complex role in the regulation of the hypothalamus-pituitary-gonadal axis in the zebrafish model. Sci Rep, 10 (1): 7632. [PMID:32376893]
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17. Dwyer AA, Hayes FJ, Plummer L, Pitteloud N, Crowley Jr WF. (2010) The long-term clinical follow-up and natural history of men with adult-onset idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab, 95 (9): 4235-43. [PMID:20591981]
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19. Jacobson O, Weiss ID, Niu G, Balboni G, Congiu C, Onnis V, Kiesewetter DO, Lattanzi R, Salvadori S, Chen X. (2011) Prokineticin receptor 1 antagonist PC-10 as a biomarker for imaging inflammatory pain. J Nucl Med, 52 (4): 600-7. [PMID:21421710]
20. Lattanzi R, Maftei D, Fullone MR, Miele R. (2021) Trypanosoma cruzi trans-sialidase induces STAT3 and ERK activation by prokineticin receptor 2 binding. Cell Biochem Funct, 39 (2): 326-334. [PMID:32892338]
21. LeCouter J, Lin R, Frantz G, Zhang Z, Hillan K, Ferrara N. (2003) Mouse endocrine gland-derived vascular endothelial growth factor: a distinct expression pattern from its human ortholog suggests different roles as a regulator of organ-specific angiogenesis. Endocrinology, 144 (6): 2606-16. [PMID:12746324]
22. LeCouter J, Lin R, Tejada M, Frantz G, Peale F, Hillan KJ, Ferrara N. (2003) The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: Localization of Bv8 receptors to endothelial cells. Proc Natl Acad Sci USA, 100 (5): 2685-90. [PMID:12604792]
23. LeCouter J, Zlot C, Tejada M, Peale F, Ferrara N. (2004) Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci USA, 101 (48): 16813-8. [PMID:15548611]
24. Lin DC, Bullock CM, Ehlert FJ, Chen JL, Tian H, Zhou QY. (2002) Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J Biol Chem, 277 (22): 19276-80. [PMID:11886876]
25. Lin R, LeCouter J, Kowalski J, Ferrara N. (2002) Characterization of endocrine gland-derived vascular endothelial growth factor signaling in adrenal cortex capillary endothelial cells. J Biol Chem, 277 (10): 8724-9. [PMID:11751915]
26. Martucci C, Franchi S, Giannini E, Tian H, Melchiorri P, Negri L, Sacerdote P. (2006) Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages. Br J Pharmacol, 147 (2): 225-34. [PMID:16299550]
27. Masuda Y, Takatsu Y, Terao Y, Kumano S, Ishibashi Y, Suenaga M, Abe M, Fukusumi S, Watanabe T, Shintani Y et al.. (2002) Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors. Biochem Biophys Res Commun, 293 (1): 396-402. [PMID:12054613]
28. Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M, Soga T, Hiyama H, Matsumoto M, Takasaki J, Kamohara M et al.. (2006) Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci USA, 103 (11): 4140-5. [PMID:16537498]
29. McCabe MJ, Gaston-Massuet C, Gregory LC, Alatzoglou KS, Tziaferi V, Sbai O, Rondard P, Masumoto KH, Nagano M, Shigeyoshi Y et al.. (2013) Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. J Clin Endocrinol Metab, 98 (3): E547-57. [PMID:23386640]
30. Monnier C, Dodé C, Fabre L, Teixeira L, Labesse G, Pin JP, Hardelin JP, Rondard P. (2009) PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum Mol Genet, 18 (1): 75-81. [PMID:18826963]
31. Moya-Plana A, Villanueva C, Laccourreye O, Bonfils P, de Roux N. (2013) PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency. Eur J Endocrinol, 168 (1): 31-7. [PMID:23082007]
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37. Prosser HM, Bradley A, Chesham JE, Ebling FJ, Hastings MH, Maywood ES. (2007) Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proc Natl Acad Sci USA, 104 (2): 648-53. [PMID:17202262]
38. Puverel S, Nakatani H, Parras C, Soussi-Yanicostas N. (2009) Prokineticin receptor 2 expression identifies migrating neuroblasts and their subventricular zone transient-amplifying progenitors in adult mice. J Comp Neurol, 512 (2): 232-42. [PMID:19003791]
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40. Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V et al.. (2012) Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab, 97 (4): E694-9. [PMID:22319038]
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44. Sarfati J, Guiochon-Mantel A, Rondard P, Arnulf I, Garcia-Piñero A, Wolczynski S, Brailly-Tabard S, Bidet M, Ramos-Arroyo M, Mathieu M et al.. (2010) A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. J Clin Endocrinol Metab, 95 (2): 659-69. [PMID:20022991]
45. Sinisi AA, Asci R, Bellastella G, Maione L, Esposito D, Elefante A, De Bellis A, Bellastella A, Iolascon A. (2008) Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report. Hum Reprod, 23 (10): 2380-4. [PMID:18596028]
46. Soga T, Matsumoto Si, Oda T, Saito T, Hiyama H, Takasaki J, Kamohara M, Ohishi T, Matsushime H, Furuichi K. (2002) Molecular cloning and characterization of prokineticin receptors. Biochim Biophys Acta, 1579 (2-3): 173-9. [PMID:12427552]
47. Song J, Li J, Liu HD, Liu W, Feng Y, Zhou XT, Li JD. (2016) Snapin interacts with G-protein coupled receptor PKR2. Biochem Biophys Res Commun, 469 (3): 501-6. [PMID:26687946]
48. Su MT, Lin SH, Chen YC, Wu LW, Kuo PL. (2013) Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy. Reproduction, 146 (1): 63-73. [PMID:23687280]
49. Svingen T, McClelland KS, Masumoto K, Sujino M, Nagano M, Shigeyoshi Y, Koopman P. (2011) Prokr2-deficient mice display vascular dysmorphology of the fetal testes: potential implications for Kallmann syndrome aetiology. Sex Dev, 5 (6): 294-303. [PMID:22223120]
50. Tabata S, Goi T, Nakazawa T, Kimura Y, Katayama K, Yamaguchi A. (2013) Endocrine gland-derived vascular endothelial growth factor strengthens cell invasion ability via prokineticin receptor 2 in colon cancer cell lines. Oncol Rep, 29 (2): 459-63. [PMID:23135359]
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