Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of targets of the Wnt pathway destruction complex in addition to beta-catenin.

ABSTRACT: The proteasomal degradation of beta-catenin mediated by the glycogen synthase kinase 3beta (GSK3beta) and destruction complex is the central step in the canonical Wnt signaling pathway. However, that there are branches of Wnt signaling pathways that do not depend on beta-catenin/Tcf-mediated transcription activation has long been understood. In this study, we hypothesized that there are many more GSK3 and destruction complex-dependent proteolytic target proteins that mediate Wnt signaling in the cell. To test this hypothesis, we have developed and carried out a screen for such candidate proteins using an in vitro expression cloning technique and biochemical reconstitution of Wnt signaling in Xenopus egg cytoplasmic extracts. Forty-two proteins have been identified as potential candidates for GSK3-regulated phosphorylation, proteasomal degradation, or both, of which 12 are strong candidates for Wnt-pathway-regulated degradation. Some of them have been reported to interact with beta-catenin and implicated in the canonical Wnt signaling pathway, and other targets identified include proteins with various cellular functions such as RNA processing, cytoskeletal dynamics, and cell metabolism. Thus, we propose that Wnt/GSK3/destruction complex signaling regulates multiple target proteins to control a broad range of cellular activities in addition to beta-catenin-mediated transcription activation.

SUBMITTER: Kim NG

PROVIDER: S-EPMC2663984 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Understanding How Wnt Influences Destruction Complex Activity and ?-Catenin Dynamics.

Project description:Despite extensive research on the canonical Wnt signaling pathway, the mechanism by which this signal downregulates the activity of destruction complexes and inhibits ?-catenin degradation remains controversial. In particular, recent attention has focused on two main competing mechanisms-inhibition of phosphorylation and inhibition of ubiquitination. Our combined experimental and theoretical analysis demonstrates that the disassembly of a fraction of the intracellular destruction complexes results in the partial inhibition of both ?-catenin phosphorylation and ubiquitination. This inhibition is spatially patterned, consistent with the relocalization of some destruction complexes to the cellular membrane upon Wnt stimulation. Moreover, in contrast to the generally accepted view that the destruction complex is highly processive, our analysis supports a distributive model, in which ?-catenin can dissociate from the complex between sequential phosphorylation events. Understanding the fundamental mechanism by which Wnt signaling is regulated provides a rational basis for tuning the pathway for scientific and therapeutic purposes.

| S-EPMC6137275 | biostudies-literature

Genome-wide identification of Wnt/β-catenin transcriptional targets during Xenopus gastrulation.

Project description:The canonical Wnt/β-catenin signaling pathway plays multiple roles during Xenopus gastrulation, including posteriorization of the neural plate, patterning of the mesoderm, and induction of the neural crest. Wnt signaling stabilizes β-catenin, which then activates target genes. However, few targets of this signaling pathway that mediate early developmental processes are known. Here we sought to identify transcriptional targets of the Wnt/β-catenin signaling pathway using a genome-wide approach. We selected putative targets using the criteria of reduced expression upon zygotic Wnt knockdown, β-catenin binding within 50kb of the gene, and expression in tissues that receive Wnt signaling. Using these criteria, we found 21 novel direct transcriptional targets of Wnt/β-catenin signaling during gastrulation and in addition have identified putative regulatory elements for further characterization in future studies.

| S-EPMC6288011 | biostudies-literature

APC controls Wnt-induced ?-catenin destruction complex recruitment in human colonocytes.

Project description:Wnt/?-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC is an essential component of a cytoplasmic protein complex that targets ?-catenin for destruction. Following Wnt ligand presentation, this complex is inhibited. However, a role for APC in this inhibition has not been shown. Here, we utilized Wnt3a-beads to locally activate Wnt co-receptors. In response, the endogenous ?-catenin destruction complex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was truncated or depleted. Non-transformed human colon epithelial cells displayed similar Wnt-induced destruction complex localization which appeared to be dependent on APC and less so on Axin. Our results expand the current model of Wnt/?-catenin signaling such that in response to Wnt, the ?-catenin destruction complex: (1) maintains composition and binding to ?-catenin, (2) moves toward the plasma membrane, and (3) requires full-length APC for this relocalization.

| S-EPMC7031393 | biostudies-literature

Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex.

Project description:The "beta-catenin destruction complex" is central to canonical Wnt/beta-catenin signaling. The scaffolding protein Axin and the tumor suppressor adenomatous polyposis coli protein (APC) are critical components of this complex, required for rapid beta-catenin turnover. We determined the crystal structure of a complex between beta-catenin and the beta-catenin-binding domain of Axin (Axin-CBD). The Axin-CBD forms a helix that occupies the groove formed by the third and fourth armadillo repeats of beta-catenin and thus precludes the simultaneous binding of other beta-catenin partners in this region. Our biochemical studies demonstrate that, when phosphorylated, the 20-amino acid repeat region of APC competes with Axin for binding to beta-catenin. We propose that a key function of APC in the beta-catenin destruction complex is to remove phosphorylated beta-catenin product from the active site.

| S-EPMC280624 | biostudies-literature

Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission.

Project description:Wnt signal transduction is controlled by the destruction complex (DC), a condensate comprising scaffold proteins and kinases that regulate β-catenin stability. Overexpressed DC scaffolds undergo liquid-liquid phase separation (LLPS), but DC mesoscale organization at endogenous expression levels and its role in β-catenin processing were previously unknown. Here, we find that DC LLPS is nucleated by the centrosome. Through a combination of CRISPR-engineered custom fluorescent tags, finite element simulations, and optogenetic tools that allow for manipulation of DC concentration and multivalency, we find that centrosomal nucleation drives processing of β-catenin by colocalizing DC components to a single reaction crucible. Enriching GSK3β partitioning on the centrosome controls β-catenin processing and prevents Wnt-driven embryonic stem cell differentiation to mesoderm. Our findings demonstrate the role of nucleators in controlling biomolecular condensates and suggest tight integration between Wnt signal transduction and the cell cycle.

| S-EPMC9457612 | biostudies-literature

A novel tumor suppressor SPINK5 targets Wnt/β-catenin signaling pathway in esophageal cancer.

Project description:Esophageal cancer is one of the most common tumor in the world, and the morbidity rate is as high as 100/100 000 in some parts of China. Therefore, it is important and urgent to explore the pathogenesis of esophageal cancer and find new therapeutic targets for esophageal cancer. In this study, we found that a novel tumor suppressor SPINK5 is significantly reduced in the development of esophageal cancer, and is closely related to the pathological differentiation and lymph node metastasis of esophageal cancer via bioinformatics analysis and esophageal cancer tissue array. Further studies have found that SPINK5 is closely related to Wnt/β-catenin signaling pathway by bioinformatics analysis and western blot. In esophageal cancer cells, SPINK5 overexpression can inhibit Wnt/β-catenin signaling pathway. Combined with LiCl or MG-132 treatment, SPINK5 can inhibit GSK3β phosphorylation and promote β-catenin protein degradation, thus inhibit Wnt/β-catenin signaling pathway. In vivo study, SPINK5 overexpression can significantly inhibit the growth of esophageal cancer cells. Our study shows that SPINK5 can inhibit the proliferation, migration, and invasion of esophageal cancer cells by inhibiting Wnt/β-catenin signaling pathway, and thus plays an important role in the development of esophageal cancer, and may serve as a treatment target of esophageal cancer.

| S-EPMC6537088 | biostudies-literature

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond ?-catenin and the destruction complex.

Project description:Wnt/?-catenin signaling is implicated in many physiological processes, including development, tissue homeostasis, and tissue regeneration. In human cancers, Wnt/?-catenin signaling is highly activated, which has led to the development of various Wnt signaling inhibitors for cancer therapies. Nonetheless, the blockade of Wnt signaling causes side effects such as impairment of tissue homeostasis and regeneration. Recently, several studies have identified cancer-specific Wnt signaling regulators. In this review, we discuss the Wnt inhibitors currently being used in clinical trials and suggest how additional cancer-specific regulators could be utilized to treat Wnt signaling-associated cancer.

| S-EPMC7062731 | biostudies-literature

Destruction complex dynamics: Wnt/?-catenin signaling alters Axin-GSK3? interactions in vivo.

Project description:The central regulator of the Wnt/?-catenin pathway is the Axin/APC/GSK3? destruction complex (DC), which, under unstimulated conditions, targets cytoplasmic ?-catenin for degradation. How Wnt activation inhibits the DC to permit ?-catenin-dependent signaling remains controversial, in part because the DC and its regulation have never been observed in vivo Using bimolecular fluorescence complementation (BiFC) methods, we have now analyzed the activity of the DC under near-physiological conditions in Drosophila By focusing on well-established patterns of Wnt/Wg signaling in the developing Drosophila wing, we have defined the sequence of events by which activated Wnt receptors induce a conformational change within the DC, resulting in modified Axin-GSK3? interactions that prevent ?-catenin degradation. Surprisingly, the nucleus is surrounded by active DCs, which principally control the degradation of ?-catenin and thereby nuclear access. These DCs are inactivated and removed upon Wnt signal transduction. These results suggest a novel mechanistic model for dynamic Wnt signal transduction in vivo.

| S-EPMC6633605 | biostudies-literature

Regulation of Transcription Factor SP1 by the ?-Catenin Destruction Complex Modulates Wnt Response.

Project description:The ubiquitous transcription factor specificity protein 1 (SP1) is heavily modified posttranslationally. These modifications are critical for switching its functions and modulation of its transcriptional activity and DNA binding and stability. However, the mechanism governing the stability of SP1 by cellular signaling pathways is not well understood. Here, we provide biochemical and functional evidence that SP1 is an integral part of the Wnt signaling pathway. We identified a phosphodegron motif in SP1 that is specific to mammals. In the absence of Wnt signaling, glycogen synthase kinase 3? (GSK3?)-mediated phosphorylation and ?-TrCP E3 ubiquitin ligase-mediated ubiquitination are required to induce SP1 degradation. When Wnt signaling is on, SP1 is stabilized in a ?-catenin-dependent manner. SP1 directly interacts with ?-catenin, and Wnt signaling induces the stabilization of SP1 by impeding its interaction with ?-TrCP and axin1, components of the destruction complex. Wnt signaling suppresses ubiquitination and subsequent proteosomal degradation of SP1. Furthermore, SP1 regulates Wnt-dependent stability of ?-catenin and their mutual stabilization is critical for target gene expression, suggesting a feedback mechanism. Upon stabilization, SP1 and ?-catenin cooccupy the promoters of TCFL2/?-catenin target genes. Collectively, this study uncovers a direct link between SP1 and ?-catenin in the Wnt signaling pathway.

| S-EPMC6206460 | biostudies-literature

Wnt/beta-catenin pathway: modulating anticancer immune response.

Project description:Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of β-catenin in signal transduction. β-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/β-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/β-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.

| S-EPMC5420131 | 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