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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F19%3A00523203" target="_blank" >RIV/68081707:_____/19:00523203 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14310/19:00108165

Result on the web

<a href="https://biosignaling.biomedcentral.com/articles/10.1186/s12964-019-0470-z" target="_blank" >https://biosignaling.biomedcentral.com/articles/10.1186/s12964-019-0470-z</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s12964-019-0470-z" target="_blank" >10.1186/s12964-019-0470-z</a>

Result language

angličtina

Original language name

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

Original language 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 (CK1 epsilon, NEK2, PLK1, CK2 alpha, RIPK4, PKC delta) 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 CK1 epsilon-induced phosphorylation of S268 and S311 for Wnt-3a-induced beta-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 C-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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell communication and signaling : CCS

ISSN

1478-811X

e-ISSN

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Volume of the periodical

17

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

21

Pages from-to

170

UT code for WoS article

000512638800001

EID of the result in the Scopus database

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