Disease relevance of PRLR

• In conclusion, activation of the PRLR is sufficient for induction of mammary carcinomas in mice, while activation of the GHR is not sufficient for mammary tumor formation [1].
• Putative binding residues, selected on the basis of a three-dimensional model of hPRL constructed in this laboratory, were mutated to alanine, and recombinant hPRL mutants produced in Escherichia coli were tested for their ability to bind to the PRLR and to stimulate Nb2 cell proliferation [2].
• Our results confirm PRLR gene expression in all tissues studied, and moreover, indicate that this expression is increased in human breast tumors vs. normal contiguous tissues [3].
• Additional studies here assessed the levels of TCR expression following PRLR stimulation and the effect of TCR activation on PRL-stimulated proliferation in lactogen-dependent pre-T Nb2-11 lymphoma cells [4].
• However, it has not been established whether this lactogenic hormone or its receptor (PRLR) have specific effects on the development of human endometriosis [5].

Psychiatry related information on PRLR

• In order to investigate whether such paradoxical agonistic behavior might result from characteristic features of the Nb2 assay (e.g. species specificity), we transfected in the same cell system the cDNA encoding the PRLR from rat or human species along with reporter genes containing PRL-responsive DNA sequences [6].
• Central infusions of the recombinant human prolactin receptor antagonist, S179D-PRL, delay the onset of maternal behavior in steroid-primed, nulliparous female rats [7].

High impact information on PRLR

• We present here the crystal structure of the 1:1 complex of hGH bound to the extracellular domain of the hPRLR [8].
• The PRL/PRL receptor complex associates with and activates several signaling networks that are shared with other members of the cytokine receptor superfamily [9].
• The actions of this ligand are mediated by at least six recognized PRL receptor isoforms found on, or secreted by, human breast epithelium [9].
• The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2 [10].
• Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice [10].

Chemical compound and disease context of PRLR

• Oestrogen and progesterone control cellular expression of the PRLR; however, elevated androgen levels in some breast-cancer patients raised the possibility that androgens may also influence breast-cancer sensitivity to lactogenic hormones [11].
• Treatment of T-47D and MCF-7 human breast cancer cells with 10 nM of the synthetic progestin ORG 2058 for 24 hr resulted in an increase in all four PRLR mRNA transcripts detected [12].
• The level of PRL receptor expression in the breast cancer cell lines was linearly related to that of the estrogen and progesterone receptors, but not to that of the androgen receptor [13].
• Coexpression and cross-regulation of the prolactin receptor and sex steroid hormone receptors in breast cancer [13].
• Development of a prolactin receptor-targeting fusion toxin using a prolactin antagonist and a recombinant form of Pseudomonas exotoxin A [14].

Biological context of PRLR

• To assess the role of tyrosine phosphorylation of the PRLR in signal transduction, several mutant forms of the PRLR in which various tyrosine residues were changed to phenylalanine were constructed and their functional properties were investigated [15].
• This interaction requires PRLR phosphorylation and the integrity of serine 349 within a conserved motif, which is similar to conserved motifs present in other substrates of SCF(beta-TrCP) [16].
• To further investigate thyroid effects in mice, we measured body temperature and thyroid-stimulating hormone in young and adult male and/or female PRLR-null mice and their normal siblings [17].
• The 5'-region of the rat PRLR gene contains at least three alternative first exons that are expressed tissue-specifically because of differential promoter usage [18].
• Real time kinetics experiments demonstrated that the ability of the analogues to form homodimeric complexes was compromised in both PRLR- and GHR-ECDs [19].

Anatomical context of PRLR

• Cell lines established from a tumor produced rPRL and expressed PRLR [1].
• Telogen follicles showed only a very weak PRLR staining of ORS keratinocytes [20].
• Upon PRL stimulation, the aglycosylated PRLR associated with Janus kinase 2 was phosphorylated and was able to activate a beta-casein gene promoter in transfected 293 fibroblast cells [21].
• PRLR expression was always greater in tumor than in normal contiguous tissue and similar in cultured mammary epithelial cells and normal breast tissues [3].
• In addition, L-PRLR [relative molecular mass (M(r)) 90,000] and I-PRLR (M(r) 50,000) protein expression was detected in human sc abdominal adipose tissue and breast adipose tissue using immunoblot analysis [22].

Associations of PRLR with chemical compounds

• Estradiol and progesterone receptor-negative tumors expressed low levels of PRLR transcripts, similar to normal breast tissue from menopausal women [3].
• Interestingly, females hemizygous for the PRLR (+/-) in their first lactation show an almost complete failure to lactate [23].
• In addition, in vitro binding assays demonstrated a direct interaction of CypA with the PRLR, in the presence or absence of cyclosporine [24].
• Although dopamine agonists allow one to study the target tissue effects of pituitary PRL, other agents, such as PRL receptor (PRLR) antagonists, are needed to analyze autocrine/paracrine loops [25].
• Immunohistochemical localization of PRL (IHL-PRL) and PRLR was performed on formalin-fixed, paraffin-embedded tissue sections [26].

Physical interactions of PRLR

• The binding affinity of hGH for the extracellular binding domain of the hPRL receptor (hPRLbp) was increased about 8000-fold by addition of 50 micromolar ZnCl2 [27].
• Adding these to the three binding determinants identified in loop 1, we now propose a complete picture of PRLR-binding site 1 of hPRL [2].
• Further, we show that SOCS-3 coimmunoprecipitates with the PRLR [28].
• CypA was co-immunoprecipitated with the PRLR in vivo from the breast epithelial cell line T47D and Chinese hamster ovary transfectants overexpressing transfected human PRLR [24].
• The PRL-receptor complex signals tyrosine phosphorylation of JAK2, a nonreceptor tyrosine kinase, which may lead to activation of PRLIF [29].

Regulatory relationships of PRLR

• Prolactin (PRL)-dependent signaling occurs as the result of ligand-induced homodimerization of the PRL receptor (PRLr) [30].
• PRLR was exclusively expressed on fibroblast-like synovial cells and lymphocytes infiltrating into the synovium in patients with RA [31].
• The deletion of F44 from hGH has the same effect as removal of residues 32-46 (approximately 200-fold loss in activity), indicating the importance of F44 in hGH when activating the hPRL receptor [32].
• PRL receptor also activates SHP-2, a cytosolic tyrosine phosphatase [33].
• These data indicated that ORG 2058 acting via the PR and DHT acting via the AR were able to induce PRLR expression in MCF-7 cells [11].

Other interactions of PRLR

• We identified a single tyrosine residue located at the C terminus of the PRLR to be necessary for in vivo activation of PRL-responsive gene transcription [15].
• In this study, we examined the ability of monomeric and dimeric forms of these ligands, human (h) PRL and hGH, and their antagonists (hPRL-G129R and hGH-G120R) to 1) bind to PRLRs; 2) induce conformational changes in PRLRs; 3) activate signaling pathways associated with the PRLR; and 4) mediate cell proliferation in vitro [34].
• These results demonstrate a novel interaction of OAS with the PRL-R and suggest a role for OAS in modulating Stat1-mediated signaling to an immediate early gene promoter [35].
• However, it cannot be excluded that the milk BP may represent a proteolytically or otherwise altered truncated form of the PRL receptor (or, less likely, the GH receptor) that maintains some binding activity, but has its immunological epitope(s) disabled [36].
• Immunohistochemistry localized the JAK/STAT proteins in the glandular epithelial cells and a subset of stromal cells, as was observed for the PRL receptor [37].

Analytical, diagnostic and therapeutic context of PRLR

• This finding suggests that PRLR-null mice could represent a valuable animal model for MTC, which could be compared with existing MTC models [17].
• In contrast to monomeric hPRL-G129R, homodimeric hPRL-G129R induced PRLR dimerization; activated Janus family of tyrosine kinases 2/signal transducer and activator of transcription 5, Ras/Raf/MAPK kinase/Erk, and phosphatidylinositol 3-kinase/Akt signaling; and stimulated Nb2 cell proliferation [34].
• OBJECTIVE: The objective of the study was to characterize the bioactivity of bbPRL in a homologous bioassay: Ba/F-3 cells stably expressing the human PRLR [38].
• We show by RT-PCR that intermediate PRLR isoform is expressed in hMSCs and that PRL exerts a significant increase in cell proliferation [39].
• RESEARCH METHODS: Genomic DNA was extracted and PCR amplification was carried out for exon 1-10 of PRLR from tumoral and adjacent non-cancerous breast tissue of tumour specimens from 38 breast cancer patients [40].

References