Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis.

ABSTRACT: Malignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt-specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signalling component and a specific regulator of pan-Wnt protein secretion, affecting both canonical and non-canonical signalling. We demonstrate that its depletion in glioma and glioma-derived stem-like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in glioma cells reduced cell migration and the capacity to form tumours in vivo. We further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. Taken together, our study identifies Evi/Wls as an essential regulator of glioma tumourigenesis, identifying a pathway-specific protein trafficking factor as an oncogene and offering novel therapeutic options to interfere with the aberrant regulation of growth factors at the site of production.

SUBMITTER: Augustin I

PROVIDER: S-EPMC3306557 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Wnt secretion protein Evi/Gpr177 promotes glioma tumorigenesis

Project description:Silencing of Evi and beta-catenin in U87MG cells

| S-ECPF-MTAB-776 | biostudies-other

Wnt secretion protein Evi/Gpr177 promotes glioma tumorigenesis

Project description:Silencing of Evi and beta-catenin in U87MG cells

2012-06-29 | E-MTAB-776 | biostudies-arrayexpress

Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion.

Project description:Wnts are evolutionarily conserved ligands that signal at short range to regulate morphogenesis, cell fate, and stem cell renewal. The first and essential steps in Wnt secretion are their O-palmitoleation and subsequent loading onto the dedicated transporter Wntless/evenness interrupted (WLS/Evi). We report the 3.2 Å resolution cryogenic electron microscopy (cryo-EM) structure of palmitoleated human WNT8A in complex with WLS. This is accompanied by biochemical experiments to probe the physiological implications of the observed association. The WLS membrane domain has close structural homology to G protein-coupled receptors (GPCRs). A Wnt hairpin inserts into a conserved hydrophobic cavity in the GPCR-like domain, and the palmitoleate protrudes between two helices into the bilayer. A conformational switch of highly conserved residues on a separate Wnt hairpin might contribute to its transfer to receiving cells. This work provides molecular-level insights into a central mechanism in animal body plan development and stem cell biology.

| S-EPMC7797000 | biostudies-literature

Interaction of the mu-opioid receptor with GPR177 (Wntless) inhibits Wnt secretion: potential implications for opioid dependence.

Project description:BackgroundOpioid agonist drugs produce analgesia. However, long-term exposure to opioid agonists may lead to opioid dependence. The analgesic and addictive properties of opioid agonist drugs are mediated primarily via the mu-opioid receptor (MOR). Opioid agonists appear to alter neuronal morphology in key brain regions implicated in the development of opioid dependence. However, the precise role of the MOR in the development of these neuronal alterations remains elusive. We hypothesize that identifying and characterizing novel MOR interacting proteins (MORIPs) may help to elucidate the underlying mechanisms involved in the development of opioid dependence.ResultsGPR177, the mammalian ortholog of Drosophila Wntless/Evi/Sprinter, was identified as a MORIP in a modified split ubiquitin yeast two-hybrid screen. GPR177 is an evolutionarily conserved protein that plays a critical role in mediating Wnt protein secretion from Wnt producing cells. The MOR/GPR177 interaction was validated in pulldown, coimmunoprecipitation, and colocalization studies using mammalian tissue culture cells. The interaction was also observed in rodent brain, where MOR and GPR177 were coexpressed in close spatial proximity within striatal neurons. At the cellular level, morphine treatment caused a shift in the distribution of GPR177 from cytosol to the cell surface, leading to enhanced MOR/GPR177 complex formation at the cell periphery and the inhibition of Wnt protein secretion.ConclusionsIt is known that chronic morphine treatment decreases dendritic arborization and hippocampal neurogenesis, and Wnt proteins are essential for these processes. We therefore propose that the morphine-mediated MOR/GPR177 interaction may result in decreased Wnt secretion in the CNS, resulting in atrophy of dendritic arbors and decreased neurogenesis. Our results demonstrate a previously unrecognized role for GPR177 in regulating cellular response to opioid drugs.

| S-EPMC2841195 | biostudies-literature

TNC upregulation promotes glioma tumourigenesis through TDG-mediated active DNA demethylation.

Project description:Gliomas represent the most predominant primary malignant tumor in central nervous system. Thymine DNA glycosylase (TDG) is a central component in active DNA demethylation. However, the specific mechanisms of TDG-mediated active DNA demethylation in gliomas remain unclear. This research indicates TDG expression is overexpressed in gliomas and correlated with poor prognosis. TDG knockdown suppressed the malignant phenotype of gliomas both in vitro and vivo. Notably, RNA-seq analysis revealed a strong association between TDG and tenascin-C (TNC). ChIP-qPCR and MeDIP-qPCR assays were undertaken to confirm that TDG participates in TNC active DNA demethylation process, revealing decreased DNA methylation levels and elevated TNC expression as a result. Silencing TNC expression also suppressed the tumor malignant phenotype in both in vitro and in vivo experiments. Additionally, simultaneous silencing of TNC reduced or even reversed the glioma promotion caused by TDG overexpression. Based on our findings, we conclude that TDG exerts an indispensable role in TNC active DNA demethylation in gliomas. The DNA demethylation process leads to alternations in TNC methylation levels and promotes its expression, thereby contributing to the development of gliomas. These results suggest a novel epigenetic therapeutic strategy targeting active DNA demethylation in gliomas.

| S-EPMC11294444 | biostudies-literature

ERAD-dependent control of the Wnt secretory factor Evi.

Project description:Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of ?-catenin by the ubiquitin-proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)-associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP-dependent manner. Ubiquitination of Evi involves the E2-conjugating enzyme UBE2J2 and the E3-ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD-dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

| S-EPMC5813261 | biostudies-literature

The role of Evi/Wntless in exporting Wnt proteins.

Project description:Intercellular communication by Wnt proteins governs many essential processes during development, tissue homeostasis and disease in all metazoans. Many context-dependent effects are initiated in the Wnt-producing cells and depend on the export of lipidated Wnt proteins. Although much focus has been on understanding intracellular Wnt signal transduction, the cellular machinery responsible for Wnt secretion became better understood only recently. After lipid modification by the acyl-transferase Porcupine, Wnt proteins bind their dedicated cargo protein Evi/Wntless for transport and secretion. Evi/Wntless and Porcupine are conserved transmembrane proteins, and their 3D structures were recently determined. In this Review, we summarise studies and structural data highlighting how Wnts are transported from the ER to the plasma membrane, and the role of SNX3-retromer during the recycling of its cargo receptor Evi/Wntless. We also describe the regulation of Wnt export through a post-translational mechanism and review the importance of Wnt secretion for organ development and cancer, and as a future biomarker.

| S-EPMC10112924 | biostudies-literature

Gpr177 deficiency impairs mammary development and prohibits Wnt-induced tumorigenesis.

Project description:Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties necessary for tumor initiation and progression. An enormous wealth of knowledge on the importance of Wnt signaling in breast development and cancer has been obtained, but the cell types responsible for production of this proliferative signal operating within normal and malignant tissues remains poorly understood. Here we report that Wnt production mediated by Gpr177 is essential for mammary morphogenesis. The loss of Gpr177 interferes with mammary stem cells, leading to deficiencies in cell proliferation and differentiation. Genetic analysis further demonstrates an indispensable role of Gpr177 in Wnt-induced tumorigenesis. The Gpr177-deficiency mice are resistant to malignant transformation. This study not only demonstrates the necessity of Wnt in mammary organogenesis but also provides a proof-of-principle for targeting of Gpr177 as a potential new treatment for human diseases with aberrant Wnt stimulation.

| S-EPMC3574013 | biostudies-literature

Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless.

Project description:Wnts play pivotal roles during development and in the mature nervous system. However, the mechanism by which Wnts traffic between cells has remained elusive. Here we demonstrate a mechanism of Wnt transmission through release of exosome-like vesicles containing the Wnt-binding protein Evenness Interrupted/Wntless/Sprinter (Evi/Wls/Srt). We show that at the Drosophila larval neuromuscular junction (NMJ), presynaptic vesicular release of Evi is required for the secretion of the Wnt, Wingless (Wg). We also show that Evi acts cell-autonomously in the postsynaptic Wnt-receiving cell to target dGRIP, a Wg-receptor-interacting protein, to postsynaptic sites. Upon Evi loss of function, dGRIP is not properly targeted to synaptic sites, interfering with postsynaptic Wnt signal transduction. These findings uncover a previously unknown cellular mechanism by which a secreted Wnt is transported across synapses by Evi-containing vesicles and reveal trafficking functions of Evi in both the Wnt-producing and the Wnt-receiving cells. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

| S-EPMC2785045 | biostudies-literature

Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.

Project description:Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

| S-EPMC4447122 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data