Prolactin receptor explained

The prolactin receptor (PRLR) is a type I cytokine receptor[1] encoded in humans by the PRLR gene on chromosome 5p13-14. It is the receptor for prolactin (PRL). The PRLR can also bind to and be activated by growth hormone (GH) and human placental lactogen (hPL). The PRLR is expressed in the mammary glands, pituitary gland, and other tissues. It plays an important role in lobuloalveolar development of the mammary glands during pregnancy and in lactation.

Structure

The prolactin receptor (PRLR) is a membrane-bound protein of the cytokine receptor superfamily. In humans, it is encoded by a single gene which contains 11 exons and is located on chromosome 5.[2] PRLR expression can be found in several tissues such as the gonads, breast, uterus, heart, liver, kidney, brain, immune cells, as well as adrenal and pituitary glands.

Several PRLR isoforms have been described in different tissues. These have varying lengths and cytoplasmic domain composition, but share identical extracellular domains, which are the regions binding to PRLR.

Diversity of PRLR is a result of transcription initiation in different sites of the PRLR promoter region. Additionally, post-translational modifications, like alternative splicing are the events that result in the different isoforms that allow for all the different actions of prolactin in the body.[3]

Signaling

The PRLR is a class 1 cytokine receptor that uses messenger pathways to control cell proliferation, migration, intracellular ion concentration and inhibit programmed cell death (apoptosis).[4] [5] PRLRs also have functions in the second messenger cascades, including:

Function

Expression of the PRLR protein is found within cells of the mammary glands[10] in accordance with its role in lactation, but also is the subject of attention for its diverse and emerging roles by its expression in adipose tissue,[11] pancreatic islet cell proliferation,[12] and immune responses.[13] The PRLR has been found to be essential for lobuloalveolar maturation of the mammary glands during pregnancy, as evidenced by the fact that PRLR knockout mice show severely impaired development of lobuloalveolar structures.[14] [15] Disruption of PRLR signaling pathways have been linked to tumorigenesis and breast cancer development.[16]

Ligands

Agonists

Antagonists

Prolactin receptor antagonists such as Del1-9-G129R-hPRL have been developed.[18] [19] [20] [21] [22]

Dopamine agonists are currently the most common methods used for treating hyperprolactinemia. However, since dopamine agonists only negatively regulate prolactin production from the pituitary gland, a few studies have tried to develop prolactin receptor antagonists for potentially treating the dopamine-resistant local hyperprolactinemia.[23] Δ1–9-G129R-hPRL is one of the prolactin receptor antagonists been studied. Δ1–9-G129R-hPRL as a mutant (inactivated) form of prolactin which exerts its antagonist effect by competing with prolactin to bind with prolactin receptors; thereby, inhibiting the agonist effects of prolactin on prolactin receptors. Besides molecular antagonists, antibodies can also potentially be used to inhibit prolactin receptor signaling. LFA102 is a monoclonal antibody that has been studied and tested for disrupting prolactin receptor's signaling in breast cancers and prostate cancers.[24] Although LFA102 has been proved sufficient to reduce prolactin receptor signaling based on in vitro and in vivo (mouse) studies, LFA102 likely has low effects on limiting tumor growth (breast and prostate cancer) as shown in phase I clinical trials.[25]

Prolactin receptor dysfunction

PRLR dysfunction has been seen to positively regulate the proliferation of malignant cells in breast cancer. Defects on prolactin receptor signalling can trigger tumour activity, rather than suppress. Signal control is monitored by a variety of genes, and the PRLR gene has been identified in the tissue of metastatic primary breast cancer cells.[26] The defect in the gene is thought to have built a resistance to chemotherapy, and has lost the ability to regulate the apoptosis of cells with mutated DNA.[27] This signalling defect then fails to promote the cellular differentiation, and promotes the upstream survival of the cancerous cells. In breast cancer, the survival of the breast epithelial cells resemble the malignant cells, characteristically known to have an increased proliferative rate.[28]

See also

Notes and References

  1. Brooks CL . Molecular mechanisms of prolactin and its receptor . Endocrine Reviews . 33 . 4 . 504–25 . August 2012 . 22577091 . 3410225 . 10.1210/er.2011-1040 . review .
  2. Brooks CL . Molecular mechanisms of prolactin and its receptor . Endocrine Reviews . 33 . 4 . 504–25 . August 2012 . 22577091 . 3410225 . 10.1210/er.2011-1040 .
  3. Minh Hung H, Dieu Hang T, Nguyen MT . Structural Investigation of Human Prolactin Receptor Transmembrane Domain Homodimerization in a Membrane Environment through Multiscale Simulations . The Journal of Physical Chemistry B . 123 . 23 . 4858–4866 . June 2019 . 31099581 . 10.1021/acs.jpcb.9b01986 . 157056703 .
  4. Dandawate P, Kaushik G, Ghosh C, Standing D, Ali Sayed AA, Choudhury S, Subramaniam D, Manzardo A, Banerjee T, Santra S, Ramamoorthy P, Butler M, Padhye SB, Baranda J, Kasi A, Sun W, Tawfik O, Coppola D, Malafa M, Umar S, Soares MJ, Saha S, Weir SJ, Dhar A, Jensen RA, Thomas SM, Anant S . 6 . Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice . Gastroenterology . 158 . 5 . 1433–1449.e27 . April 2020 . 31786131 . 7103550 . 10.1053/j.gastro.2019.11.279 .
  5. Trott JF, Schennink A, Petrie WK, Manjarin R, VanKlompenberg MK, Hovey RC . Triennial Lactation Symposium: Prolactin: The multifaceted potentiator of mammary growth and function . Journal of Animal Science . 90 . 5 . 1674–86 . May 2012 . 22205663 . 10.2527/jas.2011-4682 .
  6. Freeman ME, Kanyicska B, Lerant A, Nagy G . Prolactin: structure, function, and regulation of secretion . Physiological Reviews . 80 . 4 . 1523–631 . October 2000 . 11015620 . 10.1152/physrev.2000.80.4.1523 .
  7. Helmer RA, Panchoo M, Dertien JS, Bhakta SM, Hewetson A, Chilton BS . Prolactin-induced Jak2 phosphorylation of RUSH: a key element in Jak/RUSH signaling . Molecular and Cellular Endocrinology . 325 . 1–2 . 143–9 . August 2010 . 20562009 . 2902710 . 10.1016/j.mce.2010.05.010 .
  8. Helmer RA, Dertien JS, Chilton BS . Prolactin induces Jak2 phosphorylation of RUSHY195 . Molecular and Cellular Endocrinology . 338 . 1–2 . 79–83 . May 2011 . 21457752 . 10.1016/j.mce.2011.03.009 . 36530259 .
  9. Clevenger CV, Furth PA, Hankinson SE, Schuler LA . The role of prolactin in mammary carcinoma . Endocrine Reviews . 24 . 1 . 1–27 . February 2003 . 12588805 . 1698952 . 10.1210/er.2001-0036 .
  10. Baran N, Kelly PA, Binart N . Characterization of a prolactin-regulated gene in reproductive tissues using the prolactin receptor knockout mouse model . Biology of Reproduction . 66 . 4 . 1210–8 . April 2002 . 11906943 . 10.1095/biolreprod66.4.1210 . 22649010 . primary .
  11. Viengchareun S, Servel N, Fève B, Freemark M, Lombès M, Binart N . Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2 . PLOS ONE . 3 . 2 . e1535 . February 2008 . 18253483 . 2212135 . 10.1371/journal.pone.0001535 . free . primary . 2008PLoSO...3.1535V .
  12. Arumugam R, Fleenor D, Freemark M . Knockdown of prolactin receptors in a pancreatic beta cell line: effects on DNA synthesis, apoptosis, and gene expression . Endocrine . 46 . 3 . 568–76 . August 2014 . 24114406 . 3984618 . 10.1007/s12020-013-0073-1 . primary .
  13. Dogusan Z, Book ML, Verdood P, Yu-Lee LY, Hooghe-Peters EL . Prolactin activates interferon regulatory factor-1 expression in normal lympho-hemopoietic cells . European Cytokine Network . 11 . 3 . 435–42 . September 2000 . 11022129 . primary .
  14. Book: Horseman ND . Prolactin . 6 December 2012. Springer Science & Business Media. 978-1-4615-1683-5. 227–.
  15. Book: Bland KI, Copeland EM . The Breast: Comprehensive Management of Benign and Malignant Diseases. 9 September 2009. Elsevier Health Sciences. 978-1-4377-1121-9. 44–45.
  16. Nouhi Z, Chughtai N, Hartley S, Cocolakis E, Lebrun JJ, Ali S . Defining the role of prolactin as an invasion suppressor hormone in breast cancer cells . Cancer Research . 66 . 3 . 1824–32 . February 2006 . 16452244 . 10.1158/0008-5472.CAN-05-2292 .
  17. Bernichtein S, Kinet S, Jeay S, Llovera M, Madern D, Martial JA, Kelly PA, Goffin V . 6 . S179D-human PRL, a pseudophosphorylated human PRL analog, is an agonist and not an antagonist . Endocrinology . 142 . 9 . 3950–63 . September 2001 . 11517174 . 10.1210/endo.142.9.8369 . free .
  18. Goffin V, Touraine P, Culler MD, Kelly PA . Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia? . Nature Clinical Practice. Endocrinology & Metabolism . 2 . 10 . 571–81 . October 2006 . 17024156 . 10.1038/ncpendmet0270 . 21368033 .
  19. Jomain JB, Tallet E, Broutin I, Hoos S, van Agthoven J, Ducruix A, Kelly PA, Kragelund BB, England P, Goffin V . 6 . Structural and thermodynamic bases for the design of pure prolactin receptor antagonists: X-ray structure of Del1-9-G129R-hPRL . The Journal of Biological Chemistry . 282 . 45 . 33118–31 . November 2007 . 17785459 . 10.1074/jbc.M704364200 . free .
  20. Jacobson EM, Hugo ER, Tuttle TR, Papoian R, Ben-Jonathan N . Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor . Trends in Endocrinology and Metabolism . 21 . 11 . 691–8 . November 2010 . 20846877 . 2967606 . 10.1016/j.tem.2010.08.004 .
  21. Hansen MJ, Olsen JG, Bernichtein S, O'Shea C, Sigurskjold BW, Goffin V, Kragelund BB . Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding . Journal of Molecular Recognition . 24 . 4 . 533–47 . 2011 . 20842635 . 10.1002/jmr.1064 . 32885400 .
  22. Ferraris J, Bernichtein S, Pisera D, Goffin V . Use of prolactin receptor antagonist to better understand prolactin regulation of pituitary homeostasis . Neuroendocrinology . 98 . 3 . 171–9 . 2013 . 23969780 . 10.1159/000354701 . free . 11336/8384 . free .
  23. Karayazi Atıcı Ö, Govindrajan N, Lopetegui-González I, Shemanko CS . Prolactin: A hormone with diverse functions from mammary gland development to cancer metastasis . Seminars in Cell & Developmental Biology . 114 . 159–170 . June 2021 . 33109441 . 10.1016/j.semcdb.2020.10.005 . 225100290 .
  24. Abramicheva PA, Smirnova OV . Prolactin Receptor Isoforms as the Basis of Tissue-Specific Action of Prolactin in the Norm and Pathology . Biochemistry. Biokhimiia . 84 . 4 . 329–345 . April 2019 . 31228925 . 10.1134/S0006297919040011 . 129945003 .
  25. Goffin V, Touraine P . The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications . Expert Opinion on Therapeutic Targets . 19 . 9 . 1229–44 . September 2015 . 26063597 . 10.1517/14728222.2015.1053209 . 31029607 .
  26. Bernard V, Young J, Binart N . Prolactin - a pleiotropic factor in health and disease . Nature Reviews. Endocrinology . 15 . 6 . 356–365 . June 2019 . 30899100 . 10.1038/s41574-019-0194-6 . 84846294 .
  27. Shemanko CS . Prolactin receptor in breast cancer: marker for metastatic risk . en-US . Journal of Molecular Endocrinology . 57 . 4 . R153–R165 . November 2016 . 27658959 . 10.1530/JME-16-0150 . free .
  28. McHale K, Tomaszewski JE, Puthiyaveettil R, Livolsi VA, Clevenger CV . Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma . Modern Pathology . 21 . 5 . 565–71 . May 2008 . 18246042 . 10.1038/modpathol.2008.7 . 205199390 . free .

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