PRLR (prolactin receptor)

2011-12-01   Chon-Hwa Tsai-Morris  , Maria L Dufau  

Section on Molecular Endocrinology, Program Developmental Endocrinology, Genetics, NICHD, National Institutes of Health, Bethesda, MD 20892-4510, USA

Identity

HGNC
LOCATION
5p13.2
LOCUSID
ALIAS
HPRL,MFAB,RI-PRLR,hPRLrI
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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 name
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.

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

NCBI: 5618
MIM: 176761
HGNC: 9446
Ensembl: ENSG00000113494

Variants:

dbSNP: 5618
ClinVar: 5618
TCGA: ENSG00000113494
COSMIC: PRLR

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000113494ENST00000231423P16471
ENSG00000113494ENST00000310101P16471
ENSG00000113494ENST00000348262P16471
ENSG00000113494ENST00000397391D6R9E1
ENSG00000113494ENST00000503330D6RC67
ENSG00000113494ENST00000504500D6R9V7
ENSG00000113494ENST00000508107D6RJC8
ENSG00000113494ENST00000509140P16471
ENSG00000113494ENST00000509839D6RD41
ENSG00000113494ENST00000511486P16471
ENSG00000113494ENST00000513753P16471
ENSG00000113494ENST00000514088P16471
ENSG00000113494ENST00000514206D6R9P5
ENSG00000113494ENST00000515839D6RAN9
ENSG00000113494ENST00000542609P16471
ENSG00000113494ENST00000618457P16471
ENSG00000113494ENST00000618625D6R9E1
ENSG00000113494ENST00000619676P16471
ENSG00000113494ENST00000620785P16471

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Neuroactive ligand-receptor interactionKEGGko04080
Jak-STAT signaling pathwayKEGGko04630
Cytokine-cytokine receptor interactionKEGGhsa04060
Neuroactive ligand-receptor interactionKEGGhsa04080
Jak-STAT signaling pathwayKEGGhsa04630
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Growth hormone receptor signalingREACTOMER-HSA-982772
Prolactin receptor signalingREACTOMER-HSA-1170546

References

Pubmed IDYearTitleCitations
387136362024The Human Intermediate Prolactin Receptor I-tail Contributes Breast Oncogenesis by Targeting Ras/MAPK Pathway.0
387136362024The Human Intermediate Prolactin Receptor I-tail Contributes Breast Oncogenesis by Targeting Ras/MAPK Pathway.0
366380532023PRL-R Variants Are Not Only Associated With Prolactinomas But Also With Dopamine Agonist Resistance.1
372324892023The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate.3
379939042023The prolactin receptor gene (PRLR) is linked and associated with the risk of polycystic ovarian syndrome.0
366380532023PRL-R Variants Are Not Only Associated With Prolactinomas But Also With Dopamine Agonist Resistance.1
372324892023The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate.3
379939042023The prolactin receptor gene (PRLR) is linked and associated with the risk of polycystic ovarian syndrome.0
359221392022Breast Cancer and Prolactin - New Mechanisms and Models.5
361871162022Prolactin receptor gene transcriptional control, regulatory modalities relevant to breast cancer resistance and invasiveness.7
367449752022[Prolactin and its receptor: From animal models to pituitary pathophysiology].1
359221392022Breast Cancer and Prolactin - New Mechanisms and Models.5
361871162022Prolactin receptor gene transcriptional control, regulatory modalities relevant to breast cancer resistance and invasiveness.7
367449752022[Prolactin and its receptor: From animal models to pituitary pathophysiology].1
332599412021Immunohistochemical localization of prolactin receptor (PRLR) to Hodgkin's and Reed-Sternberg cells of Hodgkin's lymphoma.4

Citation

Chon-Hwa Tsai-Morris ; Maria L Dufau

PRLR (prolactin receptor)

Atlas Genet Cytogenet Oncol Haematol. 2011-12-01

Online version: http://atlasgeneticsoncology.org/gene/42891/js/lib/favicon/manifest.json

Historical Card

2004-10-01 PRLR (prolactin receptor) by  Chon-Hwa Tsai-Morris,Maria L Dufau 

Section on Molecular Endocrinology, Program Developmental Endocrinology, Genetics, NICHD, National Institutes of Health, Bethesda, MD 20892-4510, USA