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Cell Commun Signal
2019 Dec 23;171:170. doi: 10.1186/s12964-019-0470-z.
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Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs.
Hanáková K
,
Bernatík O
,
Kravec M
,
Micka M
,
Kumar J
,
Harnoš J
,
Ovesná P
,
Paclíková P
,
Rádsetoulal M
,
Potěšil D
,
Tripsianes K
,
Čajánek L
,
Zdráhal Z
,
Bryja V
.
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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 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. Video Abtract.
Almuedo-Castillo,
Dishevelled is essential for neural connectivity and planar cell polarity in planarians.
2011, Pubmed
Almuedo-Castillo,
Dishevelled is essential for neural connectivity and planar cell polarity in planarians.
2011,
Pubmed
Angers,
The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.
2006,
Pubmed
,
Xenbase
Bernatik,
Sequential activation and inactivation of Dishevelled in the Wnt/beta-catenin pathway by casein kinases.
2011,
Pubmed
Bernatík,
Functional analysis of dishevelled-3 phosphorylation identifies distinct mechanisms driven by casein kinase 1ϵ and frizzled5.
2014,
Pubmed
,
Xenbase
Bertrand,
cIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).
2011,
Pubmed
Bryja,
Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism.
2007,
Pubmed
Bryja,
The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic?
2017,
Pubmed
Bryja,
Beta-arrestin and casein kinase 1/2 define distinct branches of non-canonical WNT signalling pathways.
2008,
Pubmed
,
Xenbase
Čajánek,
Cep164 triggers ciliogenesis by recruiting Tau tubulin kinase 2 to the mother centriole.
2014,
Pubmed
Cervenka,
Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins.
2016,
Pubmed
Chaki,
Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.
2012,
Pubmed
Cong,
Casein kinase Iepsilon modulates the signaling specificities of dishevelled.
2004,
Pubmed
Etheridge,
Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.
2008,
Pubmed
Evangelidis,
Automated NMR resonance assignments and structure determination using a minimal set of 4D spectra.
2018,
Pubmed
Foldynová-Trantírková,
Breast cancer-specific mutations in CK1epsilon inhibit Wnt/beta-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration.
2010,
Pubmed
Fry,
A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators.
1998,
Pubmed
Fumoto,
Wnt5a signaling controls cytokinesis by correctly positioning ESCRT-III at the midbody.
2012,
Pubmed
Gammons,
Essential role of the Dishevelled DEP domain in a Wnt-dependent human-cell-based complementation assay.
2016,
Pubmed
Goetz,
The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis.
2012,
Pubmed
Golsteyn,
Cell cycle analysis and chromosomal localization of human Plk1, a putative homologue of the mitotic kinases Drosophila polo and Saccharomyces cerevisiae Cdc5.
1994,
Pubmed
Gupta,
A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.
2015,
Pubmed
Harnoš,
Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1.
2019,
Pubmed
,
Xenbase
Hoffmann,
A FlAsH-based FRET approach to determine G protein-coupled receptor activation in living cells.
2005,
Pubmed
Huang,
Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling.
2013,
Pubmed
,
Xenbase
Huang,
M-Phase Phosphoprotein 9 regulates ciliogenesis by modulating CP110-CEP97 complex localization at the mother centriole.
2018,
Pubmed
Kajimoto,
Protein kinase C {delta}-specific activity reporter reveals agonist-evoked nuclear activity controlled by Src family of kinases.
2010,
Pubmed
Kikuchi,
Dishevelled, a Wnt signalling component, is involved in mitotic progression in cooperation with Plk1.
2010,
Pubmed
Kinoshita,
PKC delta is essential for Dishevelled function in a noncanonical Wnt pathway that regulates Xenopus convergent extension movements.
2003,
Pubmed
,
Xenbase
Kishida,
Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase Iepsilon.
2001,
Pubmed
,
Xenbase
Lee,
Identification of a novel Wnt5a-CK1ɛ-Dvl2-Plk1-mediated primary cilia disassembly pathway.
2012,
Pubmed
Lee,
Conformational change of Dishevelled plays a key regulatory role in the Wnt signaling pathways.
2015,
Pubmed
,
Xenbase
Meraldi,
Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells.
2002,
Pubmed
Nusse,
Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.
2017,
Pubmed
Oda,
Binding to Cep164, but not EB1, is essential for centriolar localization of TTBK2 and its function in ciliogenesis.
2014,
Pubmed
Paclíková,
The N-Terminal Part of the Dishevelled DEP Domain Is Required for Wnt/β-Catenin Signaling in Mammalian Cells.
2017,
Pubmed
Park,
Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells.
2008,
Pubmed
,
Xenbase
Peters,
Casein kinase I transduces Wnt signals.
1999,
Pubmed
,
Xenbase
Ratcliffe,
A positive role for the PP2A catalytic subunit in Wnt signal transduction.
2000,
Pubmed
,
Xenbase
Schertel,
Systematic screening of a Drosophila ORF library in vivo uncovers Wnt/Wg pathway components.
2013,
Pubmed
Schulte,
The Frizzled family of unconventional G-protein-coupled receptors.
2007,
Pubmed
Schwarz-Romond,
The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization.
2007,
Pubmed
Semenov,
SnapShot: Noncanonical Wnt Signaling Pathways.
2007,
Pubmed
Sharma,
Dishevelled: A masterful conductor of complex Wnt signals.
2018,
Pubmed
,
Xenbase
Stejskal,
Suppression of peptide sample losses in autosampler vials.
2013,
Pubmed
Tanos,
Centriole distal appendages promote membrane docking, leading to cilia initiation.
2013,
Pubmed
Turowec,
Protein kinase CK2 is a constitutively active enzyme that promotes cell survival: strategies to identify CK2 substrates and manipulate its activity in mammalian cells.
2010,
Pubmed
Willert,
Casein kinase 2 associates with and phosphorylates dishevelled.
1997,
Pubmed
Wright,
Intrinsically disordered proteins in cellular signalling and regulation.
2015,
Pubmed
Xu,
Phosphatidylinositol phosphate kinase PIPKIγ and phosphatase INPP5E coordinate initiation of ciliogenesis.
2016,
Pubmed
Yan,
A complex of two centrosomal proteins, CAP350 and FOP, cooperates with EB1 in microtubule anchoring.
2006,
Pubmed
Yanfeng,
Functional dissection of phosphorylation of Disheveled in Drosophila.
2011,
Pubmed
Yang,
Super-resolution architecture of mammalian centriole distal appendages reveals distinct blade and matrix functional components.
2018,
Pubmed
Yang,
PP2A:B56epsilon is required for Wnt/beta-catenin signaling during embryonic development.
2003,
Pubmed
,
Xenbase
Zhang,
Inhibition of Wnt signaling by Dishevelled PDZ peptides.
2009,
Pubmed
