PROK2_HUMAN
ID PROK2_HUMAN Reviewed; 129 AA.
AC Q9HC23; Q53Z79; Q6ISR0;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 26-SEP-2001, sequence version 2.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=Prokineticin-2;
DE Short=PK2;
DE AltName: Full=Protein Bv8 homolog;
DE Flags: Precursor;
GN Name=PROK2; Synonyms=BV8;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=11259612; DOI=10.1124/mol.59.4.692;
RA Li M., Bullock C.M., Knauer D.J., Ehlert F.J., Zhou Q.-Y.;
RT "Identification of two prokineticin cDNAs: recombinant proteins potently
RT contract gastrointestinal smooth muscle.";
RL Mol. Pharmacol. 59:692-698(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=15772293; DOI=10.1124/mol.105.011619;
RA Chen J., Kuei C., Sutton S., Wilson S., Yu J., Kamme F., Mazur C.,
RA Lovenberg T., Liu C.;
RT "Identification and pharmacological characterization of prokineticin 2 beta
RT as a selective ligand for prokineticin receptor 1.";
RL Mol. Pharmacol. 67:2070-2076(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 5-129 (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=10580115; DOI=10.1016/s0014-5793(99)01473-8;
RA Wechselberger C., Puglisi R., Lepperdinger G., Boitani C., Kreil G.;
RT "The mammalian homologues of frog Bv8 are mainly expressed in
RT spermatocytes.";
RL FEBS Lett. 462:177-181(1999).
RN [6]
RP PROTEIN SEQUENCE OF 28-42.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [7]
RP VARIANTS HH4 ARG-32 AND CYS-73.
RX PubMed=17054399; DOI=10.1371/journal.pgen.0020175;
RA Dode C., Teixeira L., Levilliers J., Fouveaut C., Bouchard P.,
RA Kottler M.-L., Lespinasse J., Lienhardt-Roussie A., Mathieu M., Moerman A.,
RA Morgan G., Murat A., Toublanc J.-E., Wolczynski S., Delpech M., Petit C.,
RA Young J., Hardelin J.-P.;
RT "Kallmann syndrome: mutations in the genes encoding prokineticin-2 and
RT prokineticin receptor-2.";
RL PLoS Genet. 2:1648-1652(2006).
RN [8]
RP VARIANTS HH4 PRO-24; TYR-34; MET-50 AND CYS-73, AND CHARACTERIZATION OF
RP VARIANTS HH4 TYR-34; MET-50 AND CYS-73.
RX PubMed=18559922; DOI=10.1210/jc.2007-2654;
RA Cole L.W., Sidis Y., Zhang C., Quinton R., Plummer L., Pignatelli D.,
RA Hughes V.A., Dwyer A.A., Raivio T., Hayes F.J., Seminara S.B., Huot C.,
RA Alos N., Speiser P., Takeshita A., Van Vliet G., Pearce S.,
RA Crowley W.F. Jr., Zhou Q.Y., Pitteloud N.;
RT "Mutations in prokineticin 2 and prokineticin receptor 2 genes in human
RT gonadotrophin-releasing hormone deficiency: molecular genetics and clinical
RT spectrum.";
RL J. Clin. Endocrinol. Metab. 93:3551-3559(2008).
RN [9]
RP VARIANT HH4 PRO-24.
RX PubMed=23643382; DOI=10.1016/j.ajhg.2013.04.008;
RA Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B.,
RA Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K., Niedziela M.,
RA Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R., Hughes V.A.,
RA Kumanov P., Young J., Yialamas M.A., Hall J.E., Van Vliet G.,
RA Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S., Sidis Y., Lage K.,
RA Pitteloud N.;
RT "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in
RT individuals with congenital hypogonadotropic hypogonadism.";
RL Am. J. Hum. Genet. 92:725-743(2013).
RN [10]
RP VARIANT HH4 TYR-46.
RX PubMed=25077900; DOI=10.1210/jc.2014-2110;
RA Marcos S., Sarfati J., Leroy C., Fouveaut C., Parent P., Metz C.,
RA Wolczynski S., Gerard M., Bieth E., Kurtz F., Verier-Mine O., Perrin L.,
RA Archambeaud F., Cabrol S., Rodien P., Hove H., Prescott T., Lacombe D.,
RA Christin-Maitre S., Touraine P., Hieronimus S., Dewailly D., Young J.,
RA Pugeat M., Hardelin J.P., Dode C.;
RT "The prevalence of CHD7 missense versus truncating mutations is higher in
RT patients with Kallmann syndrome than in typical CHARGE patients.";
RL J. Clin. Endocrinol. Metab. 99:E2138-2143(2014).
CC -!- FUNCTION: May function as an output molecule from the suprachiasmatic
CC nucleus (SCN) that transmits behavioral circadian rhythm. May also
CC function locally within the SCN to synchronize output. Potently
CC contracts gastrointestinal (GI) smooth muscle.
CC -!- INTERACTION:
CC Q9HC23; Q969X1: TMBIM1; NbExp=3; IntAct=EBI-13045372, EBI-2820569;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9HC23-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9HC23-2; Sequence=VSP_005219;
CC -!- TISSUE SPECIFICITY: Expressed in the testis and, at low levels, in the
CC small intestine.
CC -!- INDUCTION: Activated by CLOCK and BMAL1 heterodimers and light;
CC inhibited by period genes (PER1, PER2 and PER3) and cryptochrome genes
CC (CRY1 and CRY2). {ECO:0000305}.
CC -!- DISEASE: Hypogonadotropic hypogonadism 4 with or without anosmia (HH4)
CC [MIM:610628]: A disorder characterized by absent or incomplete sexual
CC maturation by the age of 18 years, in conjunction with low levels of
CC circulating gonadotropins and testosterone and no other abnormalities
CC of the hypothalamic-pituitary axis. In some cases, it is associated
CC with non-reproductive phenotypes, such as anosmia, cleft palate, and
CC sensorineural hearing loss. Anosmia or hyposmia is related to the
CC absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism
CC is due to deficiency in gonadotropin-releasing hormone and probably
CC results from a failure of embryonic migration of gonadotropin-releasing
CC hormone-synthesizing neurons. In the presence of anosmia, idiopathic
CC hypogonadotropic hypogonadism is referred to as Kallmann syndrome,
CC whereas in the presence of a normal sense of smell, it has been termed
CC normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
CC {ECO:0000269|PubMed:17054399, ECO:0000269|PubMed:18559922,
CC ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The
CC disease is caused by variants affecting distinct genetic loci,
CC including the gene represented in this entry. The genetics of
CC hypogonadotropic hypogonadism involves various modes of transmission.
CC Oligogenic inheritance has been reported in some patients carrying
CC mutations in PROK2 as well as in other HH-associated genes including
CC PROKR2 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.
CC -!- SIMILARITY: Belongs to the AVIT (prokineticin) family. {ECO:0000305}.
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DR EMBL; AF333025; AAK49919.1; -; mRNA.
DR EMBL; AY349131; AAR06657.1; -; mRNA.
DR EMBL; CH471055; EAW65506.1; -; Genomic_DNA.
DR EMBL; BC069395; AAH69395.1; -; mRNA.
DR EMBL; BC096695; AAH96695.1; -; mRNA.
DR EMBL; BC098110; AAH98110.1; -; mRNA.
DR EMBL; BC098162; AAH98162.1; -; mRNA.
DR EMBL; AF182069; AAG16893.2; -; mRNA.
DR CCDS; CCDS2916.1; -. [Q9HC23-2]
DR CCDS; CCDS46868.1; -. [Q9HC23-1]
DR RefSeq; NP_001119600.1; NM_001126128.1. [Q9HC23-1]
DR RefSeq; NP_068754.1; NM_021935.3. [Q9HC23-2]
DR AlphaFoldDB; Q9HC23; -.
DR SMR; Q9HC23; -.
DR BioGRID; 121950; 13.
DR IntAct; Q9HC23; 1.
DR STRING; 9606.ENSP00000295619; -.
DR BindingDB; Q9HC23; -.
DR BioMuta; PROK2; -.
DR DMDM; 18202953; -.
DR MassIVE; Q9HC23; -.
DR PaxDb; Q9HC23; -.
DR PeptideAtlas; Q9HC23; -.
DR PRIDE; Q9HC23; -.
DR ProteomicsDB; 81626; -. [Q9HC23-1]
DR ProteomicsDB; 81627; -. [Q9HC23-2]
DR Antibodypedia; 31927; 193 antibodies from 28 providers.
DR DNASU; 60675; -.
DR Ensembl; ENST00000295619.4; ENSP00000295619.3; ENSG00000163421.9. [Q9HC23-1]
DR Ensembl; ENST00000353065.7; ENSP00000295618.3; ENSG00000163421.9. [Q9HC23-2]
DR GeneID; 60675; -.
DR KEGG; hsa:60675; -.
DR MANE-Select; ENST00000295619.4; ENSP00000295619.3; NM_001126128.2; NP_001119600.1.
DR UCSC; uc003doz.5; human. [Q9HC23-1]
DR CTD; 60675; -.
DR DisGeNET; 60675; -.
DR GeneCards; PROK2; -.
DR GeneReviews; PROK2; -.
DR HGNC; HGNC:18455; PROK2.
DR HPA; ENSG00000163421; Tissue enhanced (bone marrow, lymphoid tissue).
DR MalaCards; PROK2; -.
DR MIM; 607002; gene.
DR MIM; 610628; phenotype.
DR neXtProt; NX_Q9HC23; -.
DR OpenTargets; ENSG00000163421; -.
DR Orphanet; 478; Kallmann syndrome.
DR Orphanet; 432; Normosmic congenital hypogonadotropic hypogonadism.
DR PharmGKB; PA38540; -.
DR VEuPathDB; HostDB:ENSG00000163421; -.
DR eggNOG; ENOG502SU1D; Eukaryota.
DR GeneTree; ENSGT00940000162026; -.
DR HOGENOM; CLU_143202_1_0_1; -.
DR InParanoid; Q9HC23; -.
DR OMA; NCHPLSH; -.
DR OrthoDB; 1517288at2759; -.
DR PhylomeDB; Q9HC23; -.
DR TreeFam; TF332732; -.
DR PathwayCommons; Q9HC23; -.
DR Reactome; R-HSA-375276; Peptide ligand-binding receptors.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR SignaLink; Q9HC23; -.
DR SIGNOR; Q9HC23; -.
DR BioGRID-ORCS; 60675; 13 hits in 1036 CRISPR screens.
DR ChiTaRS; PROK2; human.
DR GenomeRNAi; 60675; -.
DR Pharos; Q9HC23; Tbio.
DR PRO; PR:Q9HC23; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q9HC23; protein.
DR Bgee; ENSG00000163421; Expressed in blood and 102 other tissues.
DR Genevisible; Q9HC23; HS.
DR GO; GO:0005576; C:extracellular region; TAS:UniProtKB.
DR GO; GO:0001664; F:G protein-coupled receptor binding; TAS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IDA:UniProtKB.
DR GO; GO:0006935; P:chemotaxis; IDA:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR GO; GO:0001935; P:endothelial cell proliferation; IDA:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; NAS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0007218; P:neuropeptide signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; TAS:UniProtKB.
DR GO; GO:0045987; P:positive regulation of smooth muscle contraction; IDA:UniProtKB.
DR GO; GO:0019233; P:sensory perception of pain; TAS:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB.
DR InterPro; IPR009523; Prokineticin.
DR InterPro; IPR023569; Prokineticin_domain.
DR PANTHER; PTHR18821; PTHR18821; 1.
DR Pfam; PF06607; Prokineticin; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Biological rhythms; Direct protein sequencing;
KW Disease variant; Disulfide bond; Hypogonadotropic hypogonadism;
KW Kallmann syndrome; Neuropeptide; Reference proteome; Secreted; Signal.
FT SIGNAL 1..27
FT /evidence="ECO:0000269|PubMed:15340161"
FT CHAIN 28..129
FT /note="Prokineticin-2"
FT /id="PRO_0000025809"
FT DISULFID 34..46
FT /evidence="ECO:0000250"
FT DISULFID 40..58
FT /evidence="ECO:0000250"
FT DISULFID 45..107
FT /evidence="ECO:0000250"
FT DISULFID 68..115
FT /evidence="ECO:0000250"
FT DISULFID 109..125
FT /evidence="ECO:0000250"
FT VAR_SEQ 75..95
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11259612,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_005219"
FT VARIANT 24
FT /note="A -> P (in HH4; phenotype consistent with Kallmann
FT syndrome; dbSNP:rs587777863)"
FT /evidence="ECO:0000269|PubMed:18559922,
FT ECO:0000269|PubMed:23643382"
FT /id="VAR_069970"
FT VARIANT 32
FT /note="G -> R (in HH4; phenotype consistent with Kallmann
FT syndrome; dbSNP:rs104893767)"
FT /evidence="ECO:0000269|PubMed:17054399"
FT /id="VAR_030955"
FT VARIANT 34
FT /note="C -> Y (in HH4; totally abolished intracellular
FT calcium mobilization; dbSNP:rs587777864)"
FT /evidence="ECO:0000269|PubMed:18559922"
FT /id="VAR_072177"
FT VARIANT 46
FT /note="C -> Y (in HH4; dbSNP:rs1427017264)"
FT /evidence="ECO:0000269|PubMed:25077900"
FT /id="VAR_072991"
FT VARIANT 50
FT /note="I -> M (in HH4; no effect on intracellular calcium
FT mobilization; dbSNP:rs1388290870)"
FT /evidence="ECO:0000269|PubMed:18559922"
FT /id="VAR_072178"
FT VARIANT 73
FT /note="R -> C (in HH4; phenotype consistent with Kallmann
FT syndrome; impaired calcium mobilization;
FT dbSNP:rs121434272)"
FT /evidence="ECO:0000269|PubMed:17054399,
FT ECO:0000269|PubMed:18559922"
FT /id="VAR_030956"
SQ SEQUENCE 129 AA; 14314 MW; 0487679E8700DA55 CRC64;
MRSLCCAPLL LLLLLPPLLL TPRAGDAAVI TGACDKDSQC GGGMCCAVSI WVKSIRICTP
MGKLGDSCHP LTRKNNFGNG RQERRKRKRS KRKKEVPFFG RRMHHTCPCL PGLACLRTSF
NRFICLAQK
