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The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

ABSTRACT: Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene disc large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE81220 | GEO | 2016/08/19

SECONDARY ACCESSION(S): PRJNA320911

REPOSITORIES: GEO

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The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Project description:Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene disc large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC. whole transcriptome RNA-seq to examine mRNAs extracted from wildtype (i.e. overexpressing lacZ) and pre-EJC-defective (i.e. overexpressing tsu RNAi) wing discs, respectively.

2016-08-19 | E-GEOD-81220 | biostudies-arrayexpress

A DLG1-ARHGAP31-CDC42 axis regulates the Wnt response in intestinal stem cells

Project description:A central factor in maintenance of tissue integrity is the response of stem cells to variations in the levels of niche signals. In the gut, intestinal stem cells (ISCs) depend on Wnt ligands for self-renewal and proliferation. Transient increases in Wnt signaling promote regeneration after injury or in inflammatory bowel diseases, whereas constitutive activation of this pathway leads to colorectal cancer. Here, we report that Discs large 1 (Dlg1) is dispensable for polarity and cellular turnover during intestinal homeostasis; however, Dlg1 is required for ISC survival in the context of increased Wnt signaling. RNA sequencing (RNAseq) and genetic mouse models demonstrated that DLG1 regulates the cellular response to increased canonical Wnt signaling. This occurs via transcriptional regulation of Arhgap31, a GTPase-activating protein that deactivates CDC42, an effector of the non-canonical Wnt pathway. These findings reveal a DLG1-ARHGAP31-CDC42 axis that is essential for the ISC response to fluctuating niche Wnt signaling.

2023-01-15 | GSE198573 | GEO

Huwe1-mediated ubiquitylation of Dvl defines a novel negative feedback loop in the Wnt signaling pathway

Project description:Wnt signaling plays a central role in development, adult tissue homeostasis and cancer. Several steps in the canonical Wnt/b-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization or protein-protein interactions of target proteins. To identify novel regulators of the Wnt/b-catenin pathway, we performed RNAi screens in C. elegans and human tissue culture cells and identified the HECT domain containing ubiquitin ligase eel-1/Huwe1 as a negative regulator of Wnt signaling. Huwe1 functions cell autonomously in signal-receiving cells and genetically acts upstream of b-catenin. Mechanistically, Huwe1 binds to and ubiquitylates the cytoplasmic Wnt pathway component Dishevelled (Dvl) in a Wnt3a and CK1e dependent manner. Huwe1 mediated ubiquitylation does not target Dvl for degradation. Instead, we found that Huwe1 decreases Dvl signaling by inhibiting Dvl multimerization. We conclude that Huwe1 is part of an evolutionarily conserved negative feedback loop in the Wnt/b-catenin pathway

2014-05-28 | PXD000781 | Pride

Dishevelled-3 protein conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1

Project description:Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we developed the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein Kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.

2019-04-02 | PXD013085 | Pride

Transcriptional response to Activating transcription factor 3 (Atf3) activity in the Drosophila eye antenna imaginal disc (EAD) epithelium.

Project description:Here we describe the transcriptional response to Atf3 expression in the EAD. Atf3 is a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the neoplastic tumor suppressors Scribble or Dlg1 induces Atf3 expression via aPKC signaling. Using ChIP-seq we have determined that Atf3 targets are enriched for roles in cytoarchitecture. Gain of Atf3 function interferes with organization of the microtubule network, thereby disturbing vesicular trafficking processes including endocytosis, and consequently alters the distribution of key polarity proteins along the apicobasal axis. Conversely, removal of Atf3 from cells lacking Dlg1 suppresses trafficking defects and restores both the normal localization of polarity determinants and epithelial differentiation. These results thus establish loss of polarity as a novel cue that induces Atf3 and demonstrate that gain of Atf3 function drives specific hallmarks of epithelial cells deficient for the Scribble polarity module.

2018-02-20 | GSE89845 | GEO

Probing the Canonicity of the Wnt/Wingless Signaling Pathway [STARR-seq]

Project description:The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a genome-wide scale the requirement for Armadillo (Arm, homolog of beta-catenin) and Pangolin (Pan, Drosophila’s TCF) in the Wnt/Wingless (Wg)-induced transcriptional response of Drosophila Kc cells. Using somatic genetics, we demonstrate that both Arm and Pan are absolutely required for mediating activation and repression of target genes. Furthermore, by means of STARR-sequencing we identified Wnt/Wg-responsive enhancer elements and found that all responsive enhancers depend on Pan. Together, our results confirm the dogma of canonical Wnt/Wg signaling and argue against the existence of distal pathway branches in this system.

2017-03-23 | GSE96542 | GEO

Dishevelled-1 regulates global transcriptomic changes in MDA-MB-231 triple negative breast cancer cells (ChIP-Seq).

Project description:Dishevelled (DVL) is a crucial component of the Wnt-signaling pathway and is vital for multiple physiological processes. Previously thought to have a primarily cytoplasmic role, the discovery of DVL translocation to the nucleus reframed how DVL is viewed functionally. Despite our advances in elucidating DVL nuclear function, further investigation is needed to determine its transcriptomic and epigenetic regulatory abilities. We show here that modification of DVL1 expression globally affects the transcriptomic landscape. Additionally, analysis of DVL1 ChIP-seq allowed us to map global binding sites and reveal the extensive reach of DVL1 binding sites. Integration of RNA-Sequencing and ChIP-Sequencing further revealed DVL1 transcription factor binding partners to regulate gene expression. These findings provide insight to nuclear DVL1 regulation of gene transcription.

2024-08-30 | GSE249320 | GEO

Dishevelled-1 regulates global transcriptomic changes in MDA-MB-231 triple negative breast cancer cells (RNA-Seq).

2024-08-30 | GSE249322 | GEO

DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2

Project description:Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney caused causes ciliary elongation and cystogenesis, and cell-based proximity labelling proteomics and fluorescence microscopy showed alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20 and polycystin-2 (PC2) were are reduced in cilia of DLG1 deficient cells compared to control cells. This phenotype was is recapitulated in vivo and rescuable by re-expression of wildtype DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggested that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

2024-05-14 | PXD051912 | Pride

Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs.

Project description:Background: Dishevelled (DVL) is an essential component of the Wnt signaling cascades. Function of DVL is controlled by phosphorylation but the molecular details are missing. DVL3 contains 131 serines and threonines whose phosphorylation generates complex barcodes underlying diverse DVL3 functions. In order to dissect the role of DVL phosphorylation we analyzed the phosphorylation of human DVL3 induced by previously reported (CK1ε, NEK2, PLK1, CK2α, RIPK4, PKCδ) and newly identified (TTBK2, Aurora A) DVL kinases. Methods: Shotgun proteomics including TiO2 enrichment of phosphorylated peptides followed by liquid chromatography tandem mass spectrometry on immunoprecipitates from HEK293T cells was used to identify and quantify phosphorylation of DVL3 protein induced by 8 kinases. Functional characterization was performed by in-cell analysis of phospho-mimicking/non phosphorylatable DVL3 mutants and supported by FRET assays and NMR spectroscopy. Results: We used quantitative mass spectrometry and calculated site occupancies and quantified phosphorylation of >80 residues. Functional validation demonstrated the importance of CK1ε-induced phosphorylation of S268 and S311 for Wnt-3a-induced β-catenin activation. S630-643 cluster phosphorylation by CK1, NEK2 or TTBK2 is essential for even subcellular distribution of DVL3 when induced by CK1 and TTBK2 but not by NEK2. Further investigation showed that NEK2 utilizes a different mechanism to promote even localization of DVL3. NEK2 triggered phosphorylation of PDZ domain at S263 and S280 prevents binding of DVL terminus to PDZ and promotes an open conformation of DVL3 that is more prone to even subcellular localization. Conclusions: We identify unique phosphorylation barcodes associated with DVL function. Our data provide an example of functional synergy between phosphorylation in structured domains and unstructured IDRs that together dictate the biological outcome.

2020-01-09 | PXD015963 | Pride

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