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Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins
I. Cervenka, J. Valnohova, O. Bernatik, J. Harnos, M. Radsetoulal, K. Sedova, K. Hanakova, D. Potesil, M. Sedlackova, A. Salasova, Z. Steinhart, S. Angers, G. Schulte, A. Hampl, Z. Zdrahal, V. Bryja,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1915 to 6 months ago
Freely Accessible Science Journals
from 1915 to 6 months ago
PubMed Central
from 1915 to 6 months ago
Europe PubMed Central
from 1915 to 6 months ago
Open Access Digital Library
from 1915-01-15
Open Access Digital Library
from 1915-01-01
- MeSH
- Autoantigens metabolism MeSH
- Centrosome metabolism MeSH
- Phosphorylation MeSH
- HEK293 Cells MeSH
- HeLa Cells MeSH
- Intracellular Signaling Peptides and Proteins metabolism MeSH
- NIMA-Related Kinases physiology MeSH
- Humans MeSH
- Dishevelled Proteins physiology MeSH
- Cell Cycle Proteins metabolism MeSH
- Nerve Tissue Proteins metabolism MeSH
- Wnt Signaling Pathway MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Department of Biochemistry and Biophysics Karolinska Institutet Stockholm 171 77 Sweden
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
Research Group Proteomics Central European Institute of Technology 62 500 Brno Czech Republic
References provided by Crossref.org
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- $a 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.
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