Paradigm-Shifters: Phosphorylated Prolactin and Short Prolactin Receptors

Huang, Kuang Tzu; Ueda, Eric; Chen, Yen Hao; Walker, Ameae M.

doi:10.1007/s10911-008-9072-x

Cited by 24 publications

(26 citation statements)

References 78 publications

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“…In addition, using cells expressing only PRL-RS, we examined the mechanism by which PRL regulates MAPK activation. Our results obtained both in vivo and in cell culture show clearly and in complete opposition to previous reports (20,22), that PRL signaling through PRL-RS deactivates both ERK1/2 and p38 MAPK pathways. We established the novel finding that this deactivation involves the association of a novel phosphatase DUPD1 with PRL-RS and with both ERK1/2 and p38 and established a novel PRL signaling mechanism through PRL-RS.…”

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confidence: 99%

“…However, a signaling role for this receptor was proposed by Das and Vonderhaar (21), who showed that activation of the mouse PRL-RS in NIH-3T3 fibroblasts induces MAPK activity and suggested that it may be involved in cell proliferation. The human PRL-RS can also activate MAPK in cultured cells, although this activation is delayed and prolonged, and therefore a role in differentiation rather than proliferation was suggested (22). Using a transgenic mouse model, Binart et al (23) reported that overexpression of PRL-RS in PRLR ϩ/Ϫ mice can rescue a mammopoiesis defect in the heterozygote mice.…”

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confidence: 99%

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Inhibition of MAPK by Prolactin Signaling through the Short Form of Its Receptor in the Ovary and Decidua

Devi

Seibold

Shehu

et al. 2011

Journal of Biological Chemistry

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Prolactin (PRL) is essential for normal reproduction and signals through two types of receptors, the short (PRL-RS) and long (PRL-RL) form. We have previously shown that transgenic mice expressing only PRL-RS (PRLRPRL, 3 a versatile hormone synthesized and secreted principally by the pituitary, plays a key role in normal ovarian development and function (reviewed in Refs. 1-4). It affects the survival and steroidogenic capacity of both the follicles and corpus luteum (1, 2, 5, 6) by activating its receptor (PRLR), a member of the cytokine receptor superfamily that lacks intrinsic tyrosine kinase activity. Two isoforms of the PRLR have been identified in several species (4, 7-10). They are generated by alternative splicing, differ in the length and composition of their cytoplasmic tail, and are referred to as short (PRL-RS) and long (PRL-RL). The most extensively characterized isoform is the PRL-RL, which transduces both mitogenic and differentiative signals (11)(12)(13)(14). It is known to activate the Jak/Stat pathway, a prototype signaling pathway used by all cytokines. As to PRL-RS, it has been cloned from several species including humans (15), rat (16), mouse (9), cow, and sheep (17). In rats, only one PRL-RS isoform is generated by alternative splicing, whereas three isoforms have been described in mice (9, 18). Among these, one clone (PR-1) is highly homologous to that of the rat (5) and contains a potential signal transduction motif (3).Conflicting results on the function of the PRL-RS have been reported. PRL-RS was originally considered as an inactive receptor that acts as a dominant negative to PRL-RL, preventing Jak2 activation and cell proliferation (19,20). However, a signaling role for this receptor was proposed by Das and Vonderhaar (21), who showed that activation of the mouse PRL-RS in NIH-3T3 fibroblasts induces MAPK activity and suggested that it may be involved in cell proliferation. The human PRL-RS can also activate MAPK in cultured cells, although this activation is delayed and prolonged, and therefore a role in differentiation rather than proliferation was suggested (22). Using a transgenic mouse model, Binart et al. (23) reported that overexpression of PRL-RS in PRLR ϩ/Ϫ mice can rescue a mammopoiesis defect in the heterozygote mice. This led to the conclusion that, in mammary glands, PRL acting through PRL-RS may mediate activation of MAPK. Generation of transgenic mice expressing only the PRL-RS in the background of PRLR null mice has recently established that in vivo activation of PRL-RS by PRL elicits profound effects in the ovary, causing a clear defect in follicular development leading to premature ovarian failure and repression of key transcription factors essential for ovarian function (5,24).Recent investigations have established a key role for MAPK in the normal development and function of the ovary. Generation of mice with granulosa cell-specific deletion of ERK1 and ERK2 (25) revealed a critical role for these kinases in granulosa * This work was supported, in whole or in par...

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confidence: 99%

Inhibition of MAPK by Prolactin Signaling through the Short Form of Its Receptor in the Ovary and Decidua

Devi

Seibold

Shehu

et al. 2011

Journal of Biological Chemistry

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“…Most of the classical cell lines were shown to express PRLR mRNA at low but detectable levels [60]. Studies in the 1990s and early 2000s reported that PRL-stimulation led to enhanced proliferation and survival of both normal and malignant prostate epithelial cells [1,36,49,53,55]. Using long-term organ cultures of normal rat prostate tissue, Ahonen and colleagues demonstrated that PRL induced the survival of androgen-deprived epithelial cells in the lateral and dorsal lobes.…”

Section: Prl/stat5 Signalingmentioning

confidence: 99%

Prolactin-Induced Prostate Tumorigenesis

Sackmann-Sala

Goffin

2014

Advances in Experimental Medicine and Biology

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The physiological role of prolactin (PRL) in the prostate gland is not clearly understood. Genetically-modified mouse models that have invalidated actors of the PRL signaling axis failed to identify an essential regulatory function on this tissue. However, a large body of evidence suggests an important role for PRL in prostate tumorigenesis. Mainly through the activation of its downstream target STAT5, PRL can induce growth and survival of prostate cancer cells and tissues in several experimental settings. In the clinic, PRL expression and STAT5 activation in human prostate tumors correlate with disease severity. Available data point to a role of local (autocrine/paracrine) rather than circulating (endocrine) PRL in the induction of disease progression. In mice, transgenic expression of PRL in the prostate leads to enhanced epithelial hyperplasia and dysplasia, with amplification of basal/stem cells which have been recently identified as prostate cancer-initiating cells. Thus, targeting PRL receptor (PRLR)/STAT5 signaling may provide an alternative therapy for the treatment of prostate cancer. Corresponding targeted therapies currently in preclinical development include antagonists or blocking antibodies for the PRLR and small molecule inhibitors directed against the tyrosine kinase JAK2 upstream of STAT5. Present efforts are aimed at validating these therapies for the treatment of prostate cancer, while understanding the mechanisms of disease progression induced by PRL/STAT5.

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“…S179D-PRL binds to both long and short receptors (17), inhibits some signaling by PRL through the long receptor isoform (18,19), and alters splicing of PRLr, favoring production of the PRLr short isoform (18)(19)(20)(21). This resulted in reduced cell proliferation in a number of in vivo and in vitro systems (18,19). In Tsc2 2/2 cells, PRL (10 mg/ml)-dependent cell proliferation was inhibited by S179D-PRL (1 mg/ml) ( Figure 5B).…”

Section: Prlr Prl and Downstream Signaling In Lam Lung Lesionsmentioning

confidence: 99%

Effects of Prolactin on TSC2-Null Eker Rat Cells and in Pulmonary Lymphangioleiomyomatosis

Terasaki¹,

Yahiro²,

Pacheco–Rodriguez³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in lymphangioleiomyomatosis cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues. Objectives: To determine the role of prolactin in signaling and proliferation in lymphangioleiomyomatosis. Methods: Prolactin levels in the sera of patients with lymphangioleiomyomatosis were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro. Measurements and Main Results: Higher prolactin levels in the sera of patients with lymphangioleiomyomatosis were associated with a faster rate of decline in FEV 1 and an increased history of pneumothorax (P , 0.01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of signal transducer and activator of transcription-1 (STAT1), STAT3, p44/42, and p38 mitogen-activated protein kinase. Tsc2 2/2 Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2 1/1 cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo. Conclusions: Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis.Keywords: proliferation; pneumothorax; pulmonary function tests; tuberous sclerosis complex Lymphangioleiomyomatosis (LAM) is an uncommon disease, predominantly found in women of childbearing age and characterized by abnormal proliferation of smooth muscle-like LAM cells, causing cystic destruction of the lung, progressive loss of pulmonary function, and, in some patients, lung transplantation or death (1, 2). LAM occurs sporadically or in association with tuberous sclerosis complex (TSC), an autosomal dominant disorder of variable penetrance associated with hamartomatous lesions (3, 4). LAM cells from patients with sporadic LAM, as well as from patients with LAM with TSC, are associated with mutations in tuberous sclerosis genes, TSC1 or TSC2, that result in activation of the mammalian target of rapamycin (mTOR) signaling pathway, leading to dysregulation of cell proliferation, size, and survival (4-7).The reasons why pulmonary disease in LAM occurs predominantly in women are not well understood, but hormones such as estrogen or testosterone may play a role. Indeed, estrogen has been shown to promote tuberin-null cell survi...

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Paradigm-Shifters: Phosphorylated Prolactin and Short Prolactin Receptors

Cited by 24 publications

References 78 publications

Inhibition of MAPK by Prolactin Signaling through the Short Form of Its Receptor in the Ovary and Decidua

Inhibition of MAPK by Prolactin Signaling through the Short Form of Its Receptor in the Ovary and Decidua

Prolactin-Induced Prostate Tumorigenesis

Effects of Prolactin on TSC2-Null Eker Rat Cells and in Pulmonary Lymphangioleiomyomatosis

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