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Multisite phosphorylation of intrinsically disordered region of DVL

ABSTRACT: When WNT binds to its receptor Frizzled (FZD) to activate the signalling, Dishevelled (DVL), the central component of Wnt signalling, is phosphorylated by redundant Casein kinase 1 (CK1) isoforms ε or δ, to transduce the signal downstream. Although the basic principles of Wnt signal transduction are known, the mechanistic aspects of DVL phosphorylation remain elusive. Here we identify Wnt-dependent multisite phosphorylation of a large and conserved serine/threonine (S/T) cluster within intrinsically disordered region (IDR), located between the PDZ and DEP domains.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Katerina Hanakova

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD063926 | Pride | 2026-04-07

REPOSITORIES: Pride

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			Action	DRS
	5015_Exp1_74IS_DDA_MaxIT250_AGC200_10_ID_1.mgf	Mgf
	5015_Exp1_74IS_DDA_MaxIT250_AGC200_10_ID_1.msf	Msf
	5015_Exp1_74IS_DDA_MaxIT250_AGC200_10_ID_1.pep.xml	Pepxml
	5015_Exp1_74IS_DDA_MaxIT250_AGC200_10_ID_1.prot.xml	Xml
	5015_Exp1_74IS_DDA_MaxIT250_AGC200_10_ID_1.raw	Raw

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Multisite phosphorylation of intrinsically disordered region of DVL

Project description:When WNT binds to its receptor Frizzled (FZD) to activate the signalling, Dishevelled (DVL), the central component of Wnt signalling, is phosphorylated by redundant Casein kinase 1 (CK1) isoforms ε or δ, to transduce the signal downstream. Although the basic principles of Wnt signal transduction are known, the mechanistic aspects of DVL phosphorylation remain elusive. Here we identify Wnt-dependent multisite phosphorylation of a large and conserved serine/threonine (S/T) cluster within intrinsically disordered region (IDR), located between the PDZ and DEP domains. The detailed analysis of the phosphorylation and its effect on the flanking domains was performed with the construct containing both domains PDZ and DEP flanking the IDR (hDVL3 PDZ-DEP, aa 243-496).

2026-04-07 | PXD063852 | Pride

Interactome analysis of DVL3 S/T cluster mutants using proximity labeling

Project description:When WNT binds to its receptor Frizzled (FZD) to activate the signalling, Dishevelled (DVL), the central component of Wnt signalling, is phosphorylated by redundant Casein kinase 1 (CK1) isoforms ε or δ, to transduce the signal downstream. Here, we mutated key serine/threonine residues in the intrinsically disordered region (IDR) between the PDZ and DEP domains. Either to alanine to prevent phosphorylation, or to glutamic acid to mimic phosphorylation, or we deleted these residues altogether. We investigated the impact of these mutations on DVL’s interactome using proximity labeling with TurboID-tagged fusion proteins at N-terminus of DVL.

2026-04-07 | PXD067002 | 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

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

CDK7-CDK11 axis in spliceosome regulation and pre-mRNA splicing – phosphopeptides dataset

Project description:Cyclin-dependent kinase 11 (CDK11) is essential for the regulation of pre-mRNA splicing via phosphorylation of the core spliceosome component SF3B1. This phosphorylation is a marker of the catalytically active spliceosomes thus it is important to identify the mechanisms that regulate CDK11 itself. Here, we report that a small subset of CDK11 is phosphorylated on the activation T-loop threonine 595 (Thr595) and is associated with the activated spliceosome on chromatin in gene bodies. Mutational analyses revealed that Thr595 is essential for the formation of the active CDK11 complex with cyclin L and SAP30BP. CDK11 transiently associates with CDK7, a transcriptional kinase that also promotes the activation of other CDKs. Inhibition of CDK7 initially decreases transcription, but longer durations of inhibition lead to production of unspliced pre-mRNAs. The onset of the CDK7-mediated splicing defect correlates with the sequential dephosphorylation of CDK11 Thr595 and SF3B1. SILAC-based phosphoproteomics upon brief CDK11 inhibition identified SF3B1, CDC5L and ESS2 as CDK11 substrates, which overlap with the previously identified CDK7 substrates in the spliceosome. In summary, our study suggests that CDK7 likely acts via CDK11 Thr595 phosphorylation to regulate pre-mRNA splicing in cells. The identification of additional CDK11 substrates points to its broader role in spliceosome regulation.

2025-12-29 | PXD062535 | Pride

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

Multisite phosphorylation of intrinsically disordered region of Dishevelled

Project description:When WNT binds to its receptor Frizzled (FZD) to activate the signaling, Dishevelled (DVL), the central component of Wnt signaling, is phosphorylated by redundant Casein kinase 1 (CK1) isoforms ε or δ, to transduce the signal downstream. Although the basic principles of Wnt signal transduction are known, the mechanistic aspects of DVL phosphorylation remain elusive. Here we identify Wnt-dependent multisite phosphorylation of a large and conserved serine/threonine (S/T) cluster within intrinsically disordered region (IDR), located between the PDZ and DEP domains. The detailed analysis of the phosphorylation and its effect on the flanking domains was performed with the construct containing both domains PDZ and DEP flanking the IDR (hDVL3 PDZ-DEP, aa 243-496).

2026-04-07 | PXD063470 | Pride

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

Proximity interactomes of human PRICKLE1, PRICKLE2 and PRICKLE3

Project description:Prickle represents an evolutionarily conserved family of proteins that is specifically linked to Wnt/planar cell polarity (PCP) signalling. This signalling pathway is crucial for the correct polarization of epithelial cells along the plane of the epithelial tissue in both Drosophila and vertebrates. While three core components of this pathway—Frizzled, Dishevelled, and Vangl—have been extensively studied, the fourth component, Prickle, has received relatively little attention. Prickle proteins play a crucial role in vertebrate development, including processes such as early embryogenesis, neurulation, body axis elongation, and organogenesis. Furthermore, Prickle proteins have been implicated in cancer biology, where they participate in the regulation of cancer cell migration, a critical step in cancer metastasis. Additionally, Prickle family has been associated with various neurological, neurodegenerative, and autoimmune diseases. The role of Prickle is complex and multifaceted; however, it remains poorly understood. Consequently, the functions of individual PRICKLE isoforms in these processes require further investigation. In this study, we present a comprehensive and validated resource of the PRICKLE1-3 interactomes that can be explored by other research groups.

2026-02-09 | PXD057854 | Pride

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