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Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9304-9. doi: 10.1073/pnas.1608783113. Epub 2016 Aug 2.

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins.

Author information

1
Department of Experimental Biology, Faculty of Science, Masaryk University, 61 137 Brno, Czech Republic;
2
Department of Experimental Biology, Faculty of Science, Masaryk University, 61 137 Brno, Czech Republic; Institute of Biophysics, Academy of Sciences of Czech Republic, 61 200 Brno, Czech Republic;
3
Research Group Proteomics, Central European Institute of Technology, 62 500 Brno, Czech Republic;
4
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 62 500 Brno, Czech Republic;
5
Department of Experimental Biology, Faculty of Science, Masaryk University, 61 137 Brno, Czech Republic; Department of Biochemistry and Biophysics, Karolinska Institutet Stockholm, 171 77, Sweden;
6
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada;
7
Department of Experimental Biology, Faculty of Science, Masaryk University, 61 137 Brno, Czech Republic; Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, 17 177 Stockholm, Sweden;
8
Research Group Proteomics, Central European Institute of Technology, 62 500 Brno, Czech Republic; National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic.
9
Department of Experimental Biology, Faculty of Science, Masaryk University, 61 137 Brno, Czech Republic; Institute of Biophysics, Academy of Sciences of Czech Republic, 61 200 Brno, Czech Republic; bryja@sci.muni.cz.

Abstract

Dishevelled (DVL) is a key scaffolding protein and a branching point in Wnt signaling pathways. Here, we present conclusive evidence that DVL regulates the centrosomal cycle. We demonstrate that DVL dishevelled and axin (DIX) domain, but not DIX domain-mediated multimerization, is essential for DVL's centrosomal localization. DVL accumulates during the cell cycle and associates with NIMA-related kinase 2 (NEK2), which is able to phosphorylate DVL at a multitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunit-associated protein 2 (CDK5RAP2) and centrosomal Nek2-associated protein 1 (C-NAP1), two proteins of the centrosomal linker. Displacement of DVL from the centrosome and its release into the cytoplasm on NEK2 phosphorylation is coupled to the removal of linker proteins, an event necessary for centrosomal separation and proper formation of the mitotic spindle. Lack of DVL prevents NEK2-controlled dissolution of loose centrosomal linker and subsequent centrosomal separation. Increased DVL levels, in contrast, sequester centrosomal NEK2 and mimic monopolar spindle defects induced by a dominant negative version of this kinase. Our study thus uncovers molecular crosstalk between centrosome and Wnt signaling.

KEYWORDS:

Dishevelled; NEK2; Wnt signaling; centrosome; linker proteins

PMID:
27486244
PMCID:
PMC4995965
DOI:
10.1073/pnas.1608783113
[Indexed for MEDLINE]
Free PMC Article

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