Prolactin receptor

Last updated
Prolactin Receptor
Identifiers
SymbolPRLR
NCBI gene 5618
HGNC 9446
OMIM 176761
PDB 1RW5
RefSeq NM_000949
UniProt P16471
Other data
Locus Chr. 5 p13-p12
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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. [18] [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. [18] 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. [24] [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

Related Research Articles

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References

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  3. ↑ Minh Hung H, Dieu Hang T, Nguyen MT (June 2019). "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. doi:10.1021/acs.jpcb.9b01986. PMID   31099581. S2CID   157056703.
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  17. ↑ Bernichtein S, Kinet S, Jeay S, Llovera M, Madern D, Martial JA, et al. (September 2001). "S179D-human PRL, a pseudophosphorylated human PRL analog, is an agonist and not an antagonist". Endocrinology. 142 (9): 3950–63. doi: 10.1210/endo.142.9.8369 . PMID   11517174.
  18. 1 2 3 Goffin V, Touraine P, Culler MD, Kelly PA (October 2006). "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. doi:10.1038/ncpendmet0270. PMID   17024156. S2CID   21368033.
  19. ↑ Jomain JB, Tallet E, Broutin I, Hoos S, van Agthoven J, Ducruix A, et al. (November 2007). "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. doi: 10.1074/jbc.M704364200 . PMID   17785459.
  20. ↑ Jacobson EM, Hugo ER, Tuttle TR, Papoian R, Ben-Jonathan N (November 2010). "Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor". Trends in Endocrinology and Metabolism. 21 (11): 691–8. doi:10.1016/j.tem.2010.08.004. PMC   2967606 . PMID   20846877.
  21. ↑ Hansen MJ, Olsen JG, Bernichtein S, O'Shea C, Sigurskjold BW, Goffin V, Kragelund BB (2011). "Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding". Journal of Molecular Recognition. 24 (4): 533–47. doi:10.1002/jmr.1064. PMID   20842635. S2CID   32885400.
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  24. 1 2 Abramicheva PA, Smirnova OV (April 2019). "Prolactin Receptor Isoforms as the Basis of Tissue-Specific Action of Prolactin in the Norm and Pathology". Biochemistry. Biokhimiia. 84 (4): 329–345. doi:10.1134/S0006297919040011. PMID   31228925. S2CID   129945003.
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  26. ↑ Bernard V, Young J, Binart N (June 2019). "Prolactin - a pleiotropic factor in health and disease". Nature Reviews. Endocrinology. 15 (6): 356–365. doi:10.1038/s41574-019-0194-6. PMID   30899100. S2CID   84846294.
  27. ↑ Shemanko CS (November 2016). "Prolactin receptor in breast cancer: marker for metastatic risk". Journal of Molecular Endocrinology. 57 (4): R153–R165. doi: 10.1530/JME-16-0150 . PMID   27658959.
  28. ↑ McHale K, Tomaszewski JE, Puthiyaveettil R, Livolsi VA, Clevenger CV (May 2008). "Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma". Modern Pathology. 21 (5): 565–71. doi: 10.1038/modpathol.2008.7 . PMID   18246042. S2CID   205199390.
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