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Journal of Molecular Endocrinology Apr 2023The prolactin receptor (PRLR) signals predominantly through the JAK2-STAT5 pathway regulating multiple physiological functions relating to fertility, lactation, and...
The prolactin receptor (PRLR) signals predominantly through the JAK2-STAT5 pathway regulating multiple physiological functions relating to fertility, lactation, and metabolism. However, the molecular pathology and role of PRLR mutations and signalling are incompletely defined, with progress hampered by a lack of reported disease-associated PRLR variants. To date, two common germline PRLR variants are reported to demonstrate constitutive activity, with one, Ile146Leu, overrepresented in benign breast disease, while a rare activating variant, Asn492Ile, is reported to be associated with an increased incidence of prolactinoma. In contrast, an inactivating germline heterozygous PRLR variant (His188Arg) was reported in a kindred with hyperprolactinaemia, while an inactivating compound heterozygous PRLR variant (Pro269Leu/Arg171Stop) was identified in an individual with hyperprolactinaemia and agalactia. We hypothesised that additional rare germline PRLR variants, identified from large-scale sequencing projects (ExAC and GnomAD), may be associated with altered in vitro PRLR signalling activity. We therefore evaluated >300 previously uncharacterised non-synonymous, germline PRLR variants and selected 10 variants for in vitro analysis based on protein prediction algorithms, proximity to known functional domains and structural modelling. Five variants, including extracellular and intracellular domain variants, were associated with altered responses when compared to the wild-type receptor. These altered responses included loss- and gain-of-function activities related to STAT5 signalling, Akt and FOXO1 activity, as well as cell viability and apoptosis. These studies provide further insight into PRLR structure-function and indicate that rare germline PRLR variants may have diverse modulating effects on PRLR signalling, although the pathophysiologic relevance of such alterations remains to be defined.
Topics: Female; Humans; Receptors, Prolactin; STAT5 Transcription Factor; Hyperprolactinemia; Signal Transduction; Prolactin; Carrier Proteins
PubMed: 36445946
DOI: 10.1530/JME-22-0164 -
Journal of Mammary Gland Biology and... Mar 2008From its traditional identity as a hormone involved in growth and differentiation of mammary epithelium and in lactation, to having a pertinent role in the development... (Review)
Review
From its traditional identity as a hormone involved in growth and differentiation of mammary epithelium and in lactation, to having a pertinent role in the development of mammary carcinoma, the peptide hormone/cytokine prolactin (PRL) has emerged as a versatile signaling molecule. There has been significant progress in our understanding of the fine working of PRL in the past several years. Notably, much effort has been concentrated on the mediator of PRL action, namely, the prolactin receptor (PRLr). The causal link between increased PRLr expression and breast cancer is being increasingly appreciated. Considering that the level of the receptor on the surface is a critical determinant of signaling output in response to PRL, the uncovering of regulatory elements that control receptor expression becomes important. The principle focus of this review is on the regulation of PRLr expression and activity in breast cancer with a brief overview of different isoforms of PRLr, their expression, signaling capabilities and the biological outcomes of PRL/PRLr signaling.
Topics: Animals; Breast Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Protein Isoforms; Receptors, Prolactin; Signal Transduction; Ubiquitin
PubMed: 18204982
DOI: 10.1007/s10911-008-9068-6 -
General and Comparative Endocrinology Jan 2021The hormone prolactin has many diverse functions across taxa such as osmoregulation, metabolism, and reproductive behavior. In ring doves, central prolactin action is...
The hormone prolactin has many diverse functions across taxa such as osmoregulation, metabolism, and reproductive behavior. In ring doves, central prolactin action is important for parental care and feeding behavior. However, there is a considerable lack of information on the distribution of the prolactin receptor (PRLR) in the avian CNS to test the hypothesis that prolactin mediates these and other functions in other birds. In order to advance this research, we collected brains from breeding and non-breeding zebra finches to map the PRLR distribution using immunohistochemistry. We found PRLRs are distributed widely across the brain, both in hypothalamic sites known to regulate parental care and feeding, but also in many non-hypothalamic sites, including the tectofugal visual pathway, song system regions, reward associated areas, and pallium. This raises the possibility that prolactin has other functions throughout the brain that are not necessarily related to feeding or parental care. In addition, we also stained brains for pSTAT5, a transcription factor which is expressed when the PRLR is activated and is used as a marker for PRLR activity. We found several notable differences in pSTAT5 activity due to the breeding state of the animal, in both directions, further supporting the hypothesis that prolactin has many diverse functions in the brain both within and outside times of breeding. Together, this study represents the first essential step to inform the design of causative studies which manipulate PRLR-expressing cells to test their role in a wide variety of behaviors and other physiological functions.
Topics: Animals; Breeding; Finches; Gene Expression Regulation; Prolactin; Receptors, Prolactin; Reproduction
PubMed: 33159912
DOI: 10.1016/j.ygcen.2020.113657 -
Journal of Mammary Gland Biology and... Jan 1997Prolactin (PRL) and growth hormone (GH) receptors are members of the cytokine receptor superfamily that are activated by ligand-induced homodimerization. On the basis of... (Review)
Review
Prolactin (PRL) and growth hormone (GH) receptors are members of the cytokine receptor superfamily that are activated by ligand-induced homodimerization. On the basis of this mechanism of activation, hormone antagonists have been developed that block the receptors in an inactive conformation. PRL and GH receptors are non-kinase receptors whose activation of signaling pathways requires participation of receptor-associated kinases, such as Janus kinases or Src kinases. Signal transduction by these receptors mainly involves the JAK/Stat pathway. In this review, we discuss the mechanism of ligand binding and receptor homodimerization as well as the involvement of molecules transducing the hormonal signal. Whenever possible, we attempt to correlate cytoplasmic features of the receptors with association and/or activation of transducer molecules or with a given biological property.
Topics: Animals; DNA-Binding Proteins; Dimerization; Enzyme Activation; Humans; Janus Kinase 2; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptors, Prolactin; Receptors, Somatotropin; STAT3 Transcription Factor; Trans-Activators
PubMed: 10887515
DOI: 10.1023/a:1026313211704 -
The Journal of Endocrinology Sep 2014The pituitary-derived hormone prolactin has been suggested to stimulate the development of atherosclerosis and cardiovascular disease through its effects on metabolism...
The pituitary-derived hormone prolactin has been suggested to stimulate the development of atherosclerosis and cardiovascular disease through its effects on metabolism and inflammation. In this study, we aimed to challenge the hypothesis that inhibition of prolactin function may beneficially affect atherosclerosis burden. Hereto, atherosclerosis-susceptible LDL receptor (Ldlr) knockout mice were transplanted with bone marrow from transgenic mice expressing the pure prolactin receptor antagonist Del1-9-G129R-hPRL or their non-transgenic littermates as control. Recipient mice expressing Del1-9-G129R-hPRL exhibited a decrease in plasma cholesterol levels (-29%; P<0.05) upon feeding a Western-type diet (WTD), which could be attributed to a marked decrease (-47%; P<0.01) in the amount of cholesterol esters associated with pro-atherogenic lipoproteins VLDL/LDL. By contrast, Del1-9-G129R-hPRL-expressing mice did not display any change in the susceptibility for atherosclerosis after 12 weeks of WTD feeding. Both the absolute atherosclerotic lesion size (223 ± 33 × 10(3) μm(2) for Del1-9-G129R-hPRL vs 259 ± 32 × 10(3) μm(2) for controls) and the lesional macrophage and collagen contents were not different between the two groups of bone marrow recipients. Importantly, Del1-9-G129R-hPRL exposure increased levels of circulating neutrophils (+91%; P<0.05), lymphocytes (+55%; P<0.05), and monocytes (+43%; P<0.05), resulting in a 49% higher (P<0.01) total blood leukocyte count. In conclusion, we have shown that prolactin receptor signaling inhibition uncouples the plasma atherogenic index from atherosclerosis susceptibility in Ldlr knockout mice. Despite an associated decrease in VLDL/LDL cholesterol levels, application of the prolactin receptor antagonist Del1-9-G129R-hPRL does not alter the susceptibility for initial development of atherosclerotic lesions probably due to the parallel increase in circulating leukocyte concentrations.
Topics: Animals; Aorta; Atherosclerosis; Bone Marrow Transplantation; Disease Susceptibility; Gene Expression; Leukocytes; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Prolactin; Receptors, LDL; Receptors, Prolactin; Recombinant Proteins; Signal Transduction
PubMed: 25063756
DOI: 10.1530/JOE-14-0343 -
Proceedings of the Society For... Jul 1994After cloning of the mammary gland prolactin (PRL) receptor cDNA, a functional assay was established using co-transfection of PRL receptor cDNA together with a milk... (Review)
Review
After cloning of the mammary gland prolactin (PRL) receptor cDNA, a functional assay was established using co-transfection of PRL receptor cDNA together with a milk protein promoter/chloramphenicol acetyl transferase (CAT) construct in Chinese hamster ovary (CHO) cells. Different mutants of the PRL receptor were tested in this CAT assay to delimit the domains in the receptor necessary for signal transduction to milk protein genes. In CHO cells stably transfected with PRL receptor cDNA, high numbers of PRL receptor are expressed. By metabolic labeling and immunoprecipitation, expressed PRL receptor was identified as a single species of 100 kDa. Using these cells, we analyzed the effects of PRL on intracellular free Ca++ concentration. PRL stimulates Ca++ entry and induces secondary Ca++ mobilization. The entry of Ca++ is a result of an increase in K+ conductance that hyperpolarizes the membranes. We have also analyzed tyrosine phosphorylation induced by PRL. In CHO cells stably transfected with PRL receptor cDNA, PRL induced a very rapid and transient tyrosine phosphorylation of a 100-kDa protein which is most probably the PRL receptor. The same finding was obtained in mammary membranes after PRL injection to lactating rabbits. Whereas tyrosine kinase inhibitors genistein and lavendustin were without effect, PRL stimulation of milk protein gene promoters was partially inhibited by 2 microM herbimycin in CHO cells co-transfected with PRL receptor cDNA and the beta lactoglobulin CAT construct. Taken together these observations indicate that the cytoplasmic domain of the PRL receptor interacts with one or several tyrosine kinases, which may represent early postreceptor events necessary for PRL signal transduction to milk protein genes.
Topics: Animals; CHO Cells; Calcium; Chloramphenicol O-Acetyltransferase; Cricetinae; DNA, Complementary; Gene Expression; Humans; Milk Proteins; Prolactin; Protein-Tyrosine Kinases; Receptors, Prolactin; Signal Transduction; Transfection
PubMed: 8016168
DOI: 10.3181/00379727-206-43763 -
Endocrine Aug 2017Prolactin is a peptide hormone mainly synthetized and secreted by the anterior pituitary gland, but also by extrapituitary tissues, such as mammary gland, decidua,... (Review)
Review
INTRODUCTION
Prolactin is a peptide hormone mainly synthetized and secreted by the anterior pituitary gland, but also by extrapituitary tissues, such as mammary gland, decidua, prostate, skin, and possibly the brain. Similarly, prolactin receptor is expressed in the pituitary gland, many peripheral tissues, and in contrast to prolactin, its receptor has been consistently detected in several brain regions, such as cerebral cortex, olfactory bulb, hypothalamus, hippocampus, amygdala, among others. Classically, prolactin function has been related to the stimulation of lactogenesis and galactopoiesis, however, it is well known that prolactin induces a wide range of functions in different brain areas.
PURPOSE
The aim of this review is to summarize recent reports on prolactin and prolactin receptor synthesis and localization, as well as recapitulate both the classic functions attributed to this hormone in the brain and the recently described functions such as neurogenesis, neurodevelopment, sleep, learning and memory, and neuroprotection.
CONCLUSION
The distribution and putative expression of prolactin and its receptors in several neuronal tissues suggests that this hormone has pleiotropic functions in the brain.
Topics: Animals; Brain Chemistry; Humans; Prolactin; Receptors, Prolactin
PubMed: 28634745
DOI: 10.1007/s12020-017-1346-x -
Advances in Experimental Medicine and... 2000Prolactin (PRL), synthesized by the anterior pituitary and to a lesser extent by numerous extrapituitary tissues, affects more physiological processes than all other... (Review)
Review
Prolactin (PRL), synthesized by the anterior pituitary and to a lesser extent by numerous extrapituitary tissues, affects more physiological processes than all other pituitary hormones combined. This hormone is involved in > 300 separate effects in various vertebrate species where its role has been well documented. The initial step in its action is the binding to a specific membrane receptor which belongs to the superfamily of class 1 cytokine receptors. The function of this receptor is mediated, at least in part, by two families of signaling molecules: Janus kinases and signal transducers and activators of transcription. PRL-binding sites have been identified in a number of cells and tissues of adult animals. Disruption of the gene for the PRL receptor has provided a new animal model with which to better understand the actions of PRL on mammary morphogenesis and mammary gland gene expression. The recent availability of genetic mouse models provides new insights into mammary developmental biology and how the action of a hormone at specific stages of development can have effects later in life on processes such as mammary development and breast cancer initiation and progression.
Topics: Animals; Breast; Female; Humans; Mammary Glands, Animal; Mice; Morphogenesis; Prolactin; Receptors, Prolactin; Signal Transduction
PubMed: 10959413
DOI: 10.1007/0-306-46832-8_10 -
The Journal of Endocrinology May 1998
Review
Topics: Animals; Cytokines; Humans; Isomerism; Lymphocytes; Prolactin; Protein-Tyrosine Kinases; Rats; Receptors, Prolactin; Signal Transduction
PubMed: 9659281
DOI: 10.1677/joe.0.1570187 -
Pituitary Sep 2003Prolactin (PRL) promotes tumor growth, as recently highlighted by the spontaneous appearance of prostate hyperplasia and mammary neoplasia in PRL transgenic mice.... (Review)
Review
Prolactin (PRL) promotes tumor growth, as recently highlighted by the spontaneous appearance of prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. Human (h)PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all PRL receptor antagonists obtained to date exhibit partial agonism, limiting their therapeutic use as full antagonists. This is the case for the first generation antagonists (the prototype of which is G129R-hPRL) that we developed ten years ago, which display antagonistic activity in some, but not all in vitro bioassays, and fail to inhibit PRL activity in transgenic mice expressing this analog. We recently developed new human PRL antagonists devoid of agonistic properties, and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as demonstrated by their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland and prostate). Finally, using transgenic mice specifically expressing PRL in the prostate, which have constitutively activated signaling cascades and prostate hyperplasia, these new PRL analogs are able to completely revert PRL-activated events to basal levels. These second generation antagonists are good candidates to be used as inhibitors of the growth-promoting actions of hPRL.
Topics: Antineoplastic Agents; Humans; Neoplasms; Prolactin; Receptors, Prolactin
PubMed: 14703018
DOI: 10.1023/b:pitu.0000004799.41035.9f