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PRLR (prolactin receptor)

Written2011-12Chon-Hwa Tsai-Morris, Maria L Dufau
Section on Molecular Endocrinology, Program Developmental Endocrinology, Genetics, NICHD, National Institutes of Health, Bethesda, MD 20892-4510, USA
This article is an update of :
2004-10Chon-Hwa Tsai-Morris, Maria L Dufau
Section on Molecular Endocrinology, Program Developmental Endocrinology, Genetics, NICHD, National Institutes of Health, Bethesda, MD 20892-4510, USA

(Note : for Links provided by Atlas : click)


LocusID (NCBI) 5618
Atlas_Id 42891
Location 5p13.2  [Link to chromosome band 5p13]
Location_base_pair Starts at 35048756 and ends at 35118122 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PRLR.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CEP44 (4q34.1)::PRLR (5p13.2)PRLR (5p13.2)::KDM3B (5q31.2)PRLR (5p13.2)::PLCXD3 (5p13.1)
PRLR (5p13.2)::PRLR (5p13.2)PRLR (5p13.2)::RHOG (11p15.4)
Note The PRLR belongs to the class I cytokine receptor family. This receptor binds the pituitary hormone prolactin with high affinity. It contains an extracellular binding domain with 2 fibronectin-like type III domains, a single transmembrane domain, and an intracellular domain required for signal transduction (via JAK-2/STAT5 and other pathways) that lacks intrinsic kinase activity.


  Figure 1. A. Localization of multiple first exons and exons 2-11 of the human prolactin receptor gene in chromosome 5p 14-13. Alternative exons 1: hE13 (generic) and hE1N1-5 (human specific); exon 2: non-coding exon; exon 3: non-coding/coding ATG translation initiation codon; exons 4-11: coding exons. B. Schematic representation of multiple exons 1 and alternative splicing to common exon 2. C. Model for E2-ERα-Sp1-C/EBPβ formation and binding to the hPIII promoter of the human prolactin receptor gene. Schematic presentation of the functional domain of ERα, Sp1 and C/EBPβ and the cognate DNA binding site of Sp1 and C/EBPβ in the hPIII promoter. Each protein is constitutively present as a homodimer dimer. ERα:AF: transactivation domain, DBD: DNA binding domain, H: hinge region, LBD: ligand binding domain; C/EBPβ:BR: basic region, LZ: leucine zipper domain; Sp1:TAD: transactivation domain, ZF: zinc finger motif.
Description The genomic size of human PRLR gene exceeds 200 kb and contains 11 exons, including six non-coding exons 1 alternative spliced to a common non-coding exon 2 and exon 3-10 that encode the full length activating long form of the receptor. Intermediate and various short forms resulting from alternative splicing. Sequences from exon 11 are present only in the short forms of the receptor S1a and S1b and their respective variants.
Transcription Transcription of human prolactin receptor gene is regulated by a multiple and tissue-specific promoter (hPIII for exons 1 species hE13 and hPN1-5 for exons 1 species hE1N1-5). The prolactin receptor promoters belong to the TATA-less/non-initiator class. The hPIII promoter contains Sp1 and C/EBP elements that bind Sp1/Sp3 and C/EBPβ required for basal and regulated transcriptional activity, while hPN1 activity is conferred by domains containing an Ets element and an NR half-site. hPN2-5 have not been characterized. Estrogen regulates PRLR transcription through the preferentially utilized PIII promoter via a non-classical ERE independent mechanism in target cells. The protein association induced by estradiol of estrogen receptor α (ERα) with DNA-bound Sp1 (constitutive) and C/EBPβ (recruited by the ERα-SP1 complex) is essential for human prolaction receptor gene transcription (figure 1C). Additional interaction between zinc fingers of Sp1 and leucine zipper of C/EBPβ stabilizes the ERα-Sp1-C/EBPβ complex. The enhanced complex formation of ERα dimer (DNA binding domain) with Sp1 (zinc finger motifs) and C/EBPβ (basic region and leucine zipper) by E2 plays an essential role in the transcriptional activation of the hPRLR gene.
Pseudogene No known pseudogenes.


  Figure 2. A. Schematic representation of human PRLR variants. Forms generated by alternative splicing. B. Structure of human prolactin receptor variants. Receptor structure of the various forms. LF: long form; IF: intermediate form; S: short forms; 10': partial exon 10; Δ#: deleted exon; #/#: exon/exon splice variant; D1, D2: N-terminal subdomain; WS: WSXWS motif; C: cysteine; Y: tyrosine; EC: extracellular domain; TM: transmembrane domain; IC: intracellular domain. Blue boxes (dark and light) in IC represent two unique sequences of short forms derived from exon 11. Amino acid number includes the signal peptide.
Description Several forms of the human prolactin receptor have been identified including the full length activating receptor (LF) and at least eight other variants (figures 2A and 2B). These variants differ by the length and composition of their extracellular and/or cytoplasmic domain. In addition to the membrane anchored prolactin receptors variants there is a soluble isoform (prolactin receptor binding protein -PRLRBP) that is generated by proteolytic cleavage of membrane bound prolactin receptor. The human prolactin receptor is composed of a single transmembrane domain, a ligand binding extracellular domain and a cytoplasmic domain which is required for signal transduction. Two disulfide-linked cysteines in the D1 subdomain are involved in ligand binding while WSXWS motif in the D2 subdomain is probably required for correct folding and cellular trafficking. Box 1, a proline rich domain highly conserved in the cytokine receptor family, is the JAK2 docking site. The activated JAK2 induced by prolactin (autophosphorylation), phosphorylates the dimerized receptor preferentially Y587 (at a consensus tyrosine phosphorylation site) which is only present in LF and ΔS1 (figure 2A). This is followed by phosphorylation, dimerization and nuclear translocation of STAT5 which causes transcriptional activation of prolactin responsive genes (i.e. β-casein, β-lactoglobulin, whey acidic protein, interferon-regulatory factor 1 and others). There are other nine tyrosines in the cytoplasmic domain (non-consensus phosphorylation sites) some of which may undergo phosphorylation and may participate in signal transduction. Box2 of unknown function is less conserved in the cytokine receptor family. Prolactin can also activate other tyrosine kinases, including Src family kinases, focal adhesion proteins, Tec kinase, and ErbB kinase. Prolactin induces the GRB2/SOS/Ras/Raf/MAPK signaling cascade. Prolactin through the long form of the receptor stimulates cell proliferation. The Δ-S1 form lacking exon 4 and 5, has reduced affinity for the hormone (due to abbreviated extracellular domain) but displays effective signal transduction. Stimulation of the intermediate form of the receptor (major deletion of exon 10, cytoplasmic domain) only with high concentrations of the ligand exhibits minor cell proliferation. The short forms of the receptor S1a and S1b derived from alternative splicing of exons 10 and 11 are inhibitory of the activation induced by prolactin through the long form of the receptor (see above). Intramolecular disulfide bonds of the prolactin receptor short form are required from its inhibitory action on the function of the long form of the receptor. Δ7/11 and Δ4-Δ7/11 isoforms do not contain transmembrane domain. Δ7/11, Δ4-Δ7/11 and PRLBP are soluble prolactin receptor. Δ4/6 S1a (Acc#. AF512796) variant encodes two open reading frames either 245 or 49 aa truncated prolactin receptor. Spliced variant S1c missing exon 10 was identified in spermatozoa (Acc#. GU133399).
Expression Prolactin receptors have been identified in number of cells and tissues including the mammary gland, organs of the reproductive system, central nervous system, pituitary, adrenal cortex, skin, bone, lung, heart, liver, pancreas, GI tract, kidney, lymphoid tissue and spermatozoa. These are also present in breast cancer tissues and cells and in other tumoral tissues/cells.
Localisation Localized in the cell membrane, but also present intracellularly at various compartments.
Function The prolactin receptor mediates prolactin signaling and triggers intracellular responses that participate in diverse biological functions including, mammary gland development (proliferation and differentiation), initiation and maintenance of lactation, regulation of water and salt balance, reproduction, gonadal steroidogenesis, preservation of sperm integrity, embryonic implantation, brain and behavior, and immune-regulation (see description).

Implicated in

Entity Various diseases
Note Changes in the expression of prolactin receptor variants were found in breast cancer tissues and cells lines when compared to adjacent normal tissues/cells. Polymorphism of prolactin receptor may be related to breast carcinoma, multiple sclerosis and systemic lupus erythematosus. Two missense variants found in patients with breast tumor, Valine for Isoleucine 76 (I76V) and Leucine for Isoleucine 146 (I146L) with gain of function were proposed to participate in breast tumorigenesis.


Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors.
Bogorad RL, Courtillot C, Mestayer C, Bernichtein S, Harutyunyan L, Jomain JB, Bachelot A, Kuttenn F, Kelly PA, Goffin V, Touraine P; Benign Breast Diseases Study Group.
Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14533-8. Epub 2008 Sep 8.
PMID 18779591
Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells.
Boutin JM, Edery M, Shirota M, Jolicoeur C, Lesueur L, Ali S, Gould D, Djiane J, Kelly PA.
Mol Endocrinol. 1989 Sep;3(9):1455-61.
PMID 2558309
Could prolactin receptor gene polymorphism play a role in pathogenesis of breast carcinoma?
Canbay E, Degerli N, Gulluoglu BM, Kaya H, Sen M, Bardakci F.
Curr Med Res Opin. 2004 Apr;20(4):533-40.
PMID 15119991
Presence and characterization of prolactin receptors in human benign breast tumours.
Di Carlo R, Muccioli G, Bellussi G, Lando D, Mussa A.
Eur J Cancer Clin Oncol. 1984 May;20(5):635-8.
PMID 6145592
A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor.
Dong J, Tsai-Morris CH, Dufau ML.
J Biol Chem. 2006 Jul 7;281(27):18825-36. Epub 2006 May 1.
PMID 16651265
Absence of prolactin receptors in normal and malignant uterine cervix.
Dowsett M, McGarrick GE, Staffurth J, Worth RW, Chapman MG, Jeffcoate SL.
Br J Obstet Gynaecol. 1984 Sep;91(9):924-6.
PMID 6089861
Expression of prolactin receptors in normal, benign, and malignant breast tissue: an immunohistological study.
Gill S, Peston D, Vonderhaar BK, Shousha S.
J Clin Pathol. 2001 Dec;54(12):956-60.
PMID 11729217
Identification of gain-of-function variants of the human prolactin receptor.
Goffin V, Bogorad RL, Touraine P.
Methods Enzymol. 2010;484:329-55.
PMID 21036240
Isolation and characterization of two novel forms of the human prolactin receptor generated by alternative splicing of a newly identified exon 11.
Hu ZZ, Meng J, Dufau ML.
J Biol Chem. 2001 Nov 2;276(44):41086-94. Epub 2001 Aug 22.
PMID 11518703
Complex 5' genomic structure of the human prolactin receptor: multiple alternative exons 1 and promoter utilization.
Hu ZZ, Zhuang L, Meng J, Tsai-Morris CH, Dufau ML.
Endocrinology. 2002 Jun;143(6):2139-42.
PMID 12021177
Complex formation and interactions between transcription factors essential for human prolactin receptor gene transcription.
Kang JH, Tsai-Morris CH, Dufau ML.
Mol Cell Biol. 2011 Aug;31(16):3208-22. Epub 2011 Jun 13.
PMID 21670145
Functional characterization of the intermediate isoform of the human prolactin receptor.
Kline JB, Roehrs H, Clevenger CV.
J Biol Chem. 1999 Dec 10;274(50):35461-8.
PMID 10585417
Characterization of a novel and functional human prolactin receptor isoform (deltaS1PRLr) containing only one extracellular fibronectin-like domain.
Kline JB, Rycyzyn MA, Clevenger CV.
Mol Endocrinol. 2002 Oct;16(10):2310-22.
PMID 12351696
Characterization and modulation of a prolactin receptor mRNA isoform in normal and tumoral human breast tissues.
Laud K, Gourdou I, Belair L, Peyrat JP, Djiane J.
Int J Cancer. 2000 Mar 15;85(6):771-6.
PMID 10709093
Prolactin and prolactin receptor gene polymorphisms in multiple sclerosis and systemic lupus erythematosus.
Mellai M, Giordano M, D'Alfonso S, Marchini M, Scorza R, Giovanna Danieli M, Leone M, Ferro I, Liguori M, Trojano M, Ballerini C, Massacesi L, Cannoni S, Bomprezzi R, Momigliano-Richiardi P.
Hum Immunol. 2003 Feb;64(2):274-84.
PMID 12559630
Human prolactin receptor variants in breast cancer: low ratio of short forms to the long-form human prolactin receptor associated with mammary carcinoma.
Meng J, Tsai-Morris CH, Dufau ML.
Cancer Res. 2004 Aug 15;64(16):5677-82.
PMID 15313907
Prolactin exerts a prosurvival effect on human spermatozoa via mechanisms that involve the stimulation of Akt phosphorylation and suppression of caspase activation and capacitation.
Pujianto DA, Curry BJ, Aitken RJ.
Endocrinology. 2010 Mar;151(3):1269-79. Epub 2009 Dec 23.
PMID 20032052
Ligand-independent homo- and heterodimerization of human prolactin receptor variants: inhibitory action of the short forms by heterodimerization.
Qazi AM, Tsai-Morris CH, Dufau ML.
Mol Endocrinol. 2006 Aug;20(8):1912-23. Epub 2006 Mar 23.
PMID 16556730
Short form 1b human prolactin receptor down-regulates expression of the long form.
Tan D, Walker AM.
J Mol Endocrinol. 2010 Mar;44(3):187-94. Epub 2009 Nov 11.
PMID 19906835
Alternative splicing to exon 11 of human prolactin receptor gene results in multiple isoforms including a secreted prolactin-binding protein.
Trott JF, Hovey RC, Koduri S, Vonderhaar BK.
J Mol Endocrinol. 2003 Feb;30(1):31-47.
PMID 12580759
Intramolecular disulfide bonds of the prolactin receptor short form are required for its inhibitory action on the function of the long form of the receptor.
Xie YL, Hassan SA, Qazi AM, Tsai-Morris CH, Dufau ML.
Mol Cell Biol. 2009 May;29(10):2546-55. Epub 2009 Mar 9.
PMID 19273600


This paper should be referenced as such :
Tsai-Morris, CH ; Dufau, ML
PRLR (prolactin receptor)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(5):361-365.
Free journal version : [ pdf ]   [ DOI ]
History of this paper:
Tsai-Morris, CH ; Dufau, ML. PRLR (prolactin receptor). Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):314-317.

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  del(9p) in Acute Lymphoblastic Leukemia

External links

HGNC (Hugo)PRLR   9446
Entrez_Gene (NCBI)PRLR    prolactin receptor
GeneCards (Weizmann)PRLR
Ensembl hg19 (Hinxton)ENSG00000113494 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000113494 [Gene_View]  ENSG00000113494 [Sequence]  chr5:35048756-35118122 [Contig_View]  PRLR [Vega]
ICGC DataPortalENSG00000113494
Genatlas (Paris)PRLR
SOURCE (Princeton)PRLR
Genetics Home Reference (NIH)PRLR
Genomic and cartography
GoldenPath hg38 (UCSC)PRLR  -     chr5:35048756-35118122 -  5p13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PRLR  -     5p13.2   [Description]    (hg19-Feb_2009)
GoldenPathPRLR - 5p13.2 [CytoView hg19]  PRLR - 5p13.2 [CytoView hg38]
Genome Data Viewer NCBIPRLR [Mapview hg19]  
OMIM176761   615554   615555   
Gene and transcription
Genbank (Entrez)AF166329 AF349939 AF416618 AF416619 AF492470
RefSeq transcript (Entrez)NM_000949 NM_001204314 NM_001204315 NM_001204316 NM_001204317 NM_001204318
Consensus coding sequences : CCDS (NCBI)PRLR
Gene ExpressionPRLR [ NCBI-GEO ]   PRLR [ EBI - ARRAY_EXPRESS ]   PRLR [ SEEK ]   PRLR [ MEM ]
Gene Expression Viewer (FireBrowse)PRLR [ Firebrowse - Broad ]
GenevisibleExpression of PRLR in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5618
GTEX Portal (Tissue expression)PRLR
Human Protein AtlasENSG00000113494-PRLR [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)PRLR
Human Protein Atlas [tissue]ENSG00000113494-PRLR [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed164 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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