Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis.
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ABSTRACT:
SUBMITTER: Bai Y
PROVIDER: S-EPMC5035919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Phosphatase of regenerating liver (PRL) is a family of protein tyrosine phosphatases (PTPs) that are anchored to the plasma membrane by prenylation. They are frequently overexpressed in various types of malignant cancers and their roles in cancer progression have received considerable attention. Mutational analyses of PRLs have shown that their intrinsic phosphatase activity is dispensable for tumor formation induced by PRL overexpression in a lung metastasis model using melanoma cells. Instead, PRLs directly bind to cyclin M (CNNM) Mg2+ exporters in the plasma membrane and potently inhibit their Mg2+ export activity, resulting in an increase in intracellular Mg2+ levels. Experiments using mammalian culture cells, mice, and C. elegans have collectively revealed that dysregulation of Mg2+ levels severely affects ATP and reactive oxygen species (ROS) levels as well as the function of Ca2+ -permeable channels. Moreover, PRL overexpression altered the optimal pH for cell proliferation from normal 7.5 to acidic 6.5, which is typically observed in malignant tumors. Here, we review the phosphatase-independent biological functions of PRLs, focusing on their interactions with CNNM Mg2+ exporters in cancer progression.
| S-EPMC9807511 | biostudies-literature
Project description:Neuroprotection is essential for the maintenance of normal physiological functions in the nervous system. This is especially true under stress conditions. Here, we demonstrate a novel protective function of PRL-1 against CO2 stimulation in Drosophila. In the absence of PRL-1, flies exhibit a permanent held-up wing phenotype upon CO2 exposure. Knockdown of the CO2 olfactory receptor, Gr21a, suppresses the phenotype. Our genetic data indicate that the wing phenotype is due to a neural dysfunction. PRL-1 physically interacts with Uex and controls Uex expression levels. Knockdown of Uex alone leads to a similar wing held-up phenotype to that of PRL-1 mutants. Uex acts downstream of PRL-1. Elevated Uex levels in PRL-1 mutants prevent the CO2-induced phenotype. PRL-1 and Uex are required for a wide range of neurons to maintain neuroprotective functions. Expression of human homologs of PRL-1 could rescue the phenotype in Drosophila, suggesting a similar function in humans.
| S-EPMC6700421 | biostudies-literature
Project description:It has been proposed that the accumulation of farnesylated phosphatase of regenerating liver-1 (PRL-1) at the plasma membrane is mediated by static electrostatic interactions of a polybasic region with acidic membrane lipids and assisted by oligomerization. Nonetheless, localization at early and recycling endosomes suggests that the recycling compartment might also contribute to its plasma membrane accumulation. Here, we investigated in live cells the dynamics of PRL-1 fused to the green fluorescent protein (GFP-PRL-1). Blocking the secretory pathway and photobleaching techniques suggested that plasma membrane accumulation of PRL-1 was not sustained by recycling endosomes but by a dynamic exchange of diffusible protein pools. Consistent with this idea, fluorescence correlation spectroscopy in cells overexpressing wild type or monomeric mutants of GFP-PRL-1 measured cytosolic and membrane-diffusing pools of protein that were not dependent on oligomerization. Endogenous expression of GFP-PRL-1 by CRISPR/Cas9 genome edition confirmed the existence of fast diffusing cytosolic and membrane pools of protein. We propose that plasma membrane PRL-1 replenishment is independent of the recycling compartment and the oligomerization state and mainly driven by fast diffusion of the cytosolic pool.
| S-EPMC7793866 | biostudies-literature
Project description:Phosphatase of regenerating liver 3 (PRL-3) is associated with cancer metastasis and has been shown to interact with the cyclin and CBS domain divalent metal cation transport mediator (CNNM) family of proteins to regulate the intracellular concentration of magnesium and other divalent metals. Despite PRL-3's importance in cancer, factors that regulate PRL-3's phosphatase activity and its interactions with CNNM proteins remain unknown. Here, we show that divalent metal ions, including magnesium, calcium, and manganese, have no impact on PRL-3's structure, stability, phosphatase activity, or CNNM binding capacity, indicating that PRL-3 does not act as a metal sensor, despite its interaction with CNNM metal transporters. In vitro approaches found that PRL-3 is a broad but not indiscriminate phosphatase, with activity toward di- and tri-nucleotides, phosphoinositols, and NADPH but not other common metabolites. Although calcium, magnesium, manganese, and zinc-binding sites were predicted near the PRL-3 active site, these divalent metals did not specifically alter PRL-3's phosphatase activity toward a generic substrate, its transition from an inactive phospho-cysteine intermediate state, or its direct binding with the CBS domain of CNNM. PRL-3's insensitivity to metal cations negates the possibility of its role as an intracellular metal content sensor for regulating CNNM activity. Further investigation is warranted to define the regulatory mechanisms governing PRL-3's phosphatase activity and CNNM interactions, as these findings could hold potential therapeutic implications in cancer treatment.
| S-EPMC10448674 | biostudies-literature
Project description:Phosphatase of regenerating liver 3 (PRL3) is suspected to be a causative factor toward cellular metastasis when in excess. To date, the molecular basis for PRL3 function remains an enigma, making efforts at distilling a concerted mechanism for PRL3-mediated metastatic dissemination very difficult. We previously discovered that PRL3 expressing cells exhibit a pronounced increase in protein tyrosine phosphorylation. Here we take an unbiased mass spectrometry-based approach toward identifying the phosphoproteins exhibiting enhanced levels of tyrosine phosphorylation with a goal to define the "PRL3-mediated signaling network." Phosphoproteomic data support intracellular activation of an extensive signaling network normally governed by extracellular ligand-activated transmembrane growth factor, cytokine, and integrin receptors in the PRL3 cells. Additionally, data implicate the Src tyrosine kinase as the major intracellular kinase responsible for "hijacking" this network and provide strong evidence that aberrant Src activation is a major consequence of PRL3 overexpression. Importantly, the data support a PDGF(?/?)-, Eph (A2/B3/B4)-, and Integrin (?1/?5)-receptor array as being the predominant network coordinator in the PRL3 cells, corroborating a PRL3-induced mesenchymal-state. Within this network, we find that tyrosine phosphorylation is increased on a multitude of signaling effectors responsible for Rho-family GTPase, PI3K-Akt, STAT, and ERK activation, linking observations made by the field as a whole under Src as a primary signal transducer. Our phosphoproteomic data paint the most comprehensive picture to date of how PRL3 drives prometastatic molecular events through Src activation.
| S-EPMC3861722 | biostudies-literature
Project description:BackgroundOverexpression of phosphatase of regenerating liver 3 (PRL-3) has been implicated in gastric cancer (GC) metastasis. Epidemiological studies have evaluated the relationship between PRL-3 expression and prognosis in GC. However, results still remains controversial. In this study, a meta-analysis was performed to evaluate the association of PRL-3 expression with overall survival (OS) and clinicopathological characteristics.MethodsLiterature databases were searched to identify eligible studies dated until April 2013. Summary hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the association.ResultsA total of 1380 GC patients from six studies were included in the meta-analysis. Overall, the combined HR estimate for OS in a random-effect model was 1.89 (95% CI = 1.38-2.60; P<0.001). Results showed that PRL-3 overexpression was significantly associated with OS, indicating that it may be a biomarker for poor prognosis of GC. Both subgroup and sensitivity analyses further identified the prognostic role of PRL-3 expression in GC patients. Moreover, PRL-3 overexpression was significantly associated with tumor stage (OR = 2.25; 95% CI = 1.63-3.12; P<0.001), depth of invasion (OR = 2.03; 95% CI = 1.38-2.98; P<0.001), vascular invasion (OR = 2.52; 95% CI = 1.79-3.56; P<0.001), lymphatic invasion (OR = 3.74; 95% CI = 2.49-5.63; P<0.001), and lymph node metastasis (OR = 4.56; 95% CI = 2.37-8.76; P<0.001). However, when age, sex, tumor size, and tumor differentiation were considered, no obvious association was observed.ConclusionsThis meta-analysis reveals significant association of PRL-3 overexpression with OS and some clinicopathological features in GC. PRL-3 may be a predicative factor of poor prognosis and aggressive tumor behavior in GC patients.
| S-EPMC3799911 | biostudies-literature
Project description:BACKGROUND: PRL-3 is a member of phosphatases of regenerating liver family, characterized by phosphatase active domain and C-terminal prenylation motif. Overexpression of PRL-3 has been implicated in multiple cancers. Here we examined the clinical significance of PRL-3 in gastric cancer together with its metastatic biological functions utilizing different structural mutants. METHODS: PRL-3 expression was analyzed immunohistochemically in 196 gastric cancer patients and 21 cases of liver metastasis. A series of wild type PRL-3 or its mutant plasmids were expressed in BGC823 cells to investigate the relationship between its catalytic activity, cellular localization and metastatic potential in vitro. RESULTS: Positive staining of PRL-3 was observed in 19.4% (38/196) gastric cancer tissues compared with 76.2% (16/21) in liver metastasis. Statistical analysis revealed that PRL-3 expression correlated with lymph node metastasis and vascular invasion (P<0.05). Patients with high PRL-3 expression showed poorer 5-year overall survival (P=0.011). Wild type PRL-3 expressing cells resulted in enhanced migration and invasion ability, which were greatly crippled in form of PRL-3(C104S) or PRL-3(?CAAX) mutants accompanied with its alteration in subcellular localization. CONCLUSIONS: Metastasis associated protein PRL-3 may serve as a potential prognostic biomarker in human gastric cancer. Both the phosphatase catalytic activity and cellular localization are critical for its function.
| S-EPMC3878674 | biostudies-literature
Project description:Background:Phosphatase of regenerating liver-3 (PRL-3) is implicated in oncogenesis of hematological and solid cancers. PRL-3 expression increases metastatic potential, invasiveness and is associated with poor prognosis. With this study, we aimed to show a possible oncogenic role of PRL-3 in classical Hodgkin lymphoma (cHL). Methods:PRL-3 expression was measured in 25 cHL patients by immunohistochemistry and gene expression was analyzed from microdissected malignant cells. We knocked down PRL-3 in the cHL cell lines L1236 and HDLM2 and used small molecular inhibitors against PRL-3 to investigate proliferation, migration and cytokine production. Results:PRL-3 protein was expressed in 16% of patient samples. In three different gene expression datasets, PRL-3 was significantly overexpressed compared to normal controls. PRL-3 knockdown reduced proliferation, viability and Mcl-1 expression in L1236, but not in HDLM2 cells. Thienopyridone, a small molecule inhibitor of PRL-3, reduced proliferation of both L1236 and HDLM2. PRL-3 affected IL-13 secretion and enhanced STAT6 signaling. IL-13 stimulation partially rescued proliferation in L1236 cells after knockdown of PRL-3. PRL-3 knockdown reduced migration in both L1236 and HDLM2 cells. Conclusion:PRL-3 was overexpressed in a subset of cHL patients. Inhibition of PRL-3 increased IL-13 cytokine production and reduced migration, proliferation and viability. The effects could be mediated through regulation of the anti-apoptotic molecule Mcl-1 and a feedback loop of IL-13 mediated activation of STAT6. This point to a role for PRL-3 in the pathogenesis of Hodgkin lymphoma, and PRL-3 could be a possible new drug target.
| S-EPMC5894150 | biostudies-literature
Project description:Phosphatase of regenerating liver-1 (PRL-1) belongs to a unique subfamily of protein tyrosine phosphatases (PTPases) associated with oncogenic and metastatic phenotypes. While considerable evidence supports a role for PRL-1 in promoting proliferation, the biological regulators and effectors of PRL-1 activity remain unknown. PRL-1 activity is inhibited by disulfide bond formation at the active site in vitro, suggesting PRL-1 may be susceptible to redox regulation in vivo. Because PRL-1 has been observed to localize to several different subcellular locations and cellular redox conditions vary with tissue type, age, stage of cell cycle, and subcellular location, we determined the reduction potential of the active site disulfide bond that controls phosphatase activity to improve our understanding of the function of PRL-1 in various cellular environments. We used high-resolution solution NMR spectroscopy to measure the potential and found it to be -364.3 +/- 1.5 mV. Because normal cellular environments range from -170 to -320 mV, we concluded that nascent PRL-1 would be primarily oxidized inside cells. Our studies show that a significant conformational change accompanies activation, suggesting a post-translational modification may alter the reduction potential, conferring activity. We further demonstrate that alteration of the C-terminus renders the protein reduced and active in vitro, implying the C-terminus is an important regulator of PRL-1 function. These data provide a basis for understanding how subcellular localization regulates the activity of PRL-1 and, with further investigation, may help reveal how PRL-1 promotes unique outcomes in different cellular systems, including proliferation in both normal and diseased states.
| S-EPMC2759777 | biostudies-literature
Project description:BackgroundVascular abnormalities in the ovary cause infertility accompanied by ovarian insufficiency due to a microenvironment of barren ovarian tissues. Placenta-derived mesenchymal stem cells (PD-MSCs, Naïve) treatment in ovarian dysfunction shows angiogenic effect, however, the therapeutic mechanism between ovarian function and vascular remodeling still unclear. Therefore, we examined whether by phosphatase regenerating liver-1 (PRL-1), which is correlated with angiogenesis in reproductive systems, overexpressed PD-MSCs could maximize the angiogenic effects in an ovarian tissues injured of rat model with partial ovariectomy and their therapeutic mechanism by enhanced vascular function via PDGF signaling.MethodsPD-MSCsPRL-1 (PRL-1) were generated by nonviral AMAXA gene delivery system and analyzed the vascular remodeling and follicular development in ovary. One week after Sprague-Dawley (SD) rats ovariectomy, Naïve and PRL-1 was transplanted. The animals were sacrificed at 1, 3 and 5 weeks after transplantation and vascular remodeling and follicular development were analyzed. Also, human umbilical vein endothelial cells (HUVECs) and ovarian explantation culture were performed to prove the specific effects and mechanism of PRL-1.ResultsVascular structures in ovarian tissues (e.g., number of vessels, thickness and lumen area) showed changes in the Naïve and PRL-1-overexpressed PD-MSC (PRL-1) transplantation (Tx) groups compared to the nontransplantation (NTx) group. Especially, PRL-1 induce to increase the expression of platelet-derived growth factor (PDGF), which plays a role in vascular remodeling as well as follicular development, compared to the NTx. Also, the expression of genes related to pericyte and vascular permeability in arteries was significantly enhanced in the PRL-1 compared to the NTx (p < 0.05). PRL-1 enhanced the vascular formation and permeability of human umbilical vein endothelial cells (HUVECs) via activated the PDGF signaling pathway.ConclusionsOur results show that PRL-1 restored ovarian function by enhanced vascular function via PDGF signaling pathway. These findings offer new insight into the effects of functionally enhanced stem cell therapy for reproductive systems and should provide new avenues to develop more efficient therapies in degenerative medicine.
| S-EPMC8900363 | biostudies-literature