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Gene Review

PRLR  -  prolactin receptor

Homo sapiens

Synonyms: HPRL, MFAB, PRL-R, Prolactin receptor, hPRLrI
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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


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


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


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].


  1. Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. Wennbo, H., Gebre-Medhin, M., Gritli-Linde, A., Ohlsson, C., Isaksson, O.G., Törnell, J. J. Clin. Invest. (1997) [Pubmed]
  2. Characterization of lactogen receptor-binding site 1 of human prolactin. Kinet, S., Goffin, V., Mainfroid, V., Martial, J.A. J. Biol. Chem. (1996) [Pubmed]
  3. Increased expression of prolactin receptor gene assessed by quantitative polymerase chain reaction in human breast tumors versus normal breast tissues. Touraine, P., Martini, J.F., Zafrani, B., Durand, J.C., Labaille, F., Malet, C., Nicolas, A., Trivin, C., Postel-Vinay, M.C., Kuttenn, F., Kelly, P.A. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  4. Prolactin receptor signaling: shared components with the T-cell antigen receptor in Nb2 lymphoma cells. Krumenacker, J.S., Montgomery, D.W., Buckley, D.J., Gout, P.W., Buckley, A.R. Endocrine (1998) [Pubmed]
  5. Prolactin receptor in human endometriotic tissues. Martinez, L.B., Leyva, M.Z., Romero, I.C. Acta obstetricia et gynecologica Scandinavica. (2002) [Pubmed]
  6. Antagonistic properties of human prolactin analogs that show paradoxical agonistic activity in the Nb2 bioassay. Goffin, V., Kinet, S., Ferrag, F., Binart, N., Martial, J.A., Kelly, P.A. J. Biol. Chem. (1996) [Pubmed]
  7. Central infusions of the recombinant human prolactin receptor antagonist, S179D-PRL, delay the onset of maternal behavior in steroid-primed, nulliparous female rats. Bridges, R., Rigero, B., Byrnes, E., Yang, L., Walker, A. Endocrinology (2001) [Pubmed]
  8. The X-ray structure of a growth hormone-prolactin receptor complex. Somers, W., Ultsch, M., De Vos, A.M., Kossiakoff, A.A. Nature (1994) [Pubmed]
  9. The role of prolactin in mammary carcinoma. Clevenger, C.V., Furth, P.A., Hankinson, S.E., Schuler, L.A. Endocr. Rev. (2003) [Pubmed]
  10. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Bole-Feysot, C., Goffin, V., Edery, M., Binart, N., Kelly, P.A. Endocr. Rev. (1998) [Pubmed]
  11. Androgen regulation of prolactin-receptor gene expression in MCF-7 and MDA-MB-453 human breast cancer cells. Ormandy, C.J., Clarke, C.L., Kelly, P.A., Sutherland, R.L. Int. J. Cancer (1992) [Pubmed]
  12. The effect of progestins on prolactin receptor gene transcription in human breast cancer cells. Ormandy, C.J., Graham, J., Kelly, P.A., Clarke, C.L., Sutherland, R.L. DNA Cell Biol. (1992) [Pubmed]
  13. Coexpression and cross-regulation of the prolactin receptor and sex steroid hormone receptors in breast cancer. Ormandy, C.J., Hall, R.E., Manning, D.L., Robertson, J.F., Blamey, R.W., Kelly, P.A., Nicholson, R.I., Sutherland, R.L. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  14. Development of a prolactin receptor-targeting fusion toxin using a prolactin antagonist and a recombinant form of Pseudomonas exotoxin A. Langenheim, J.F., Chen, W.Y. Breast Cancer Res. Treat. (2005) [Pubmed]
  15. A single phosphotyrosine residue of the prolactin receptor is responsible for activation of gene transcription. Lebrun, J.J., Ali, S., Goffin, V., Ullrich, A., Kelly, P.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  16. Negative regulation of prolactin receptor stability and signaling mediated by SCF(beta-TrCP) E3 ubiquitin ligase. Li, Y., Kumar, K.G., Tang, W., Spiegelman, V.S., Fuchs, S.Y. Mol. Cell. Biol. (2004) [Pubmed]
  17. Medullary thyroid carcinoma arises in the absence of prolactin signaling. Kedzia, C., Lacroix, L., Ameur, N., Ragot, T., Kelly, P.A., Caillou, B., Binart, N. Cancer Res. (2005) [Pubmed]
  18. Regulation of prolactin receptor (PRLR) gene expression in insulin-producing cells. Prolactin and growth hormone activate one of the rat prlr gene promoters via STAT5a and STAT5b. Galsgaard, E.D., Nielsen, J.H., Møldrup, A. J. Biol. Chem. (1999) [Pubmed]
  19. Novel recombinant analogues of bovine placental lactogen. G133K and G133R provide a tool to understand the difference between the action of prolactin and growth hormone receptors. Helman, D., Staten, N.R., Grosclaude, J., Daniel, N., Nespoulous, C., Djiane, J., Gertler, A. J. Biol. Chem. (1998) [Pubmed]
  20. Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen. Foitzik, K., Krause, K., Nixon, A.J., Ford, C.A., Ohnemus, U., Pearson, A.J., Paus, R. Am. J. Pathol. (2003) [Pubmed]
  21. N-glycosylation of the prolactin receptor is not required for activation of gene transcription but is crucial for its cell surface targeting. Buteau, H., Pezet, A., Ferrag, F., Perrot-Applanat, M., Kelly, P.A., Edery, M. Mol. Endocrinol. (1998) [Pubmed]
  22. Identification of functional prolactin (PRL) receptor gene expression: PRL inhibits lipoprotein lipase activity in human white adipose tissue. Ling, C., Svensson, L., Odén, B., Weijdegård, B., Edén, B., Edén, S., Billig, H. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  23. The role of prolactin and growth hormone in mammary gland development. Kelly, P.A., Bachelot, A., Kedzia, C., Hennighausen, L., Ormandy, C.J., Kopchick, J.J., Binart, N. Mol. Cell. Endocrinol. (2002) [Pubmed]
  24. A novel and functional interaction between cyclophilin A and prolactin receptor. Syed, F., Rycyzyn, M.A., Westgate, L., Clevenger, C.V. Endocrine (2003) [Pubmed]
  25. Prolactin receptor antagonists. Kuo, C.B., Coss, D., Walker, A.M. Endocrine (1998) [Pubmed]
  26. Prolactin as a local growth promoter in patients with breast cancer: GCRI experience. Bhatavdekar, J.M., Patel, D.D., Shah, N.G., Vora, H.H., Suthar, T.P., Ghosh, N., Chikhlikar, P.R., Trivedi, T.I. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. (2000) [Pubmed]
  27. Zinc mediation of the binding of human growth hormone to the human prolactin receptor. Cunningham, B.C., Bass, S., Fuh, G., Wells, J.A. Science (1990) [Pubmed]
  28. Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor. Dif, F., Saunier, E., Demeneix, B., Kelly, P.A., Edery, M. Endocrinology (2001) [Pubmed]
  29. Receptor to nucleus signaling by prolactin and interleukin 2 via activation of latent DNA-binding factors. Gilmour, K.C., Reich, N.C. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  30. Characterization of a novel and functional human prolactin receptor isoform (deltaS1PRLr) containing only one extracellular fibronectin-like domain. Kline, J.B., Rycyzyn, M.A., Clevenger, C.V. Mol. Endocrinol. (2002) [Pubmed]
  31. Prolactin locally produced by synovium infiltrating T lymphocytes induces excessive synovial cell functions in patients with rheumatoid arthritis. Nagafuchi, H., Suzuki, N., Kaneko, A., Asai, T., Sakane, T. J. Rheumatol. (1999) [Pubmed]
  32. Different elements of mini-helix 1 are required for human growth hormone or prolactin action via the prolactin receptor. Peterson, F.C., Brooks, C.L. Protein Eng. Des. Sel. (2004) [Pubmed]
  33. Dominant negative variants of the SHP-2 tyrosine phosphatase inhibit prolactin activation of Jak2 (janus kinase 2) and induction of Stat5 (signal transducer and activator of transcription 5)-dependent transcription. Berchtold, S., Volarevic, S., Moriggl, R., Mercep, M., Groner, B. Mol. Endocrinol. (1998) [Pubmed]
  34. Two wrongs can make a right: dimers of prolactin and growth hormone receptor antagonists behave as agonists. Langenheim, J.F., Tan, D., Walker, A.M., Chen, W.Y. Mol. Endocrinol. (2006) [Pubmed]
  35. Association of 2',5'-oligoadenylate synthetase with the prolactin (PRL) receptor: alteration in PRL-inducible stat1 (signal transducer and activator of transcription 1) signaling to the IRF-1 (interferon-regulatory factor 1) promoter. McAveney, K.M., Book, M.L., Ling, P., Chebath, J., Yu-Lee, L. Mol. Endocrinol. (2000) [Pubmed]
  36. A growth hormone/prolactin-binding protein in human milk. Mercado, M., Baumann, G. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  37. Expression of functional prolactin receptors in nonpregnant human endometrium: janus kinase-2, signal transducer and activator of transcription-1 (STAT1), and STAT5 proteins are phosphorylated after stimulation with prolactin. Jabbour, H.N., Critchley, H.O., Boddy, S.C. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  38. Human macroprolactin displays low biological activity via its homologous receptor in a new sensitive bioassay. Glezer, A., Soares, C.R., Vieira, J.G., Giannella-Neto, D., Ribela, M.T., Goffin, V., Bronstein, M.D. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  39. Prolactin is a component of the human synovial liquid and modulates the growth and chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. Ogueta, S., Muñoz, J., Obregon, E., Delgado-Baeza, E., García-Ruiz, J.P. Mol. Cell. Endocrinol. (2002) [Pubmed]
  40. Could prolactin receptor gene polymorphism play a role in pathogenesis of breast carcinoma? Canbay, E., Degerli, N., Gulluoglu, B.M., Kaya, H., Sen, M., Bardakci, F. Current medical research and opinion. (2004) [Pubmed]
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