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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. 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).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Katerina Hanakova

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD063852 | Pride | 2026-04-07

REPOSITORIES: Pride

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			Action	DRS
	4156_Gomoryova_65min-IS_TOP06HCD_10_ID_01_Recal.mgf	Mgf
	4156_Gomoryova_65min-IS_TOP06HCD_10_ID_01_Recal.msf	Msf
	4156_Gomoryova_65min-IS_TOP06HCD_10_ID_01_Recal.pep.xml	Pepxml
	4156_Gomoryova_65min-IS_TOP06HCD_10_ID_01_Recal.prot.xml	Xml
	4156_Gomoryova_65min-IS_TOP06HCD_10_ID_01_Recal.raw	Raw

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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).

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Multisite phosphorylation of intrinsically disordered region of DVL

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

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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.

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