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

Igor Cervenka; Jana Valnohova; Ondrej Bernatik; Jakub Harnos; Matej Radsetoulal; Katerina Sedova; Katerina Hanakova; David Potesil; Miroslava Sedlackova; Alena Salasova; Zachary Steinhart; Stephane Angers; Gunnar Schulte; Ales Hampl; Zbynek Zdrahal; Vitezslav Bryja

doi:10.1073/pnas.1608783113

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

Igor Cervenka, Jana Valnohova, Ondrej Bernatik, Jakub Harnos, Matej Radsetoulal, Katerina Sedova, Katerina Hanakova, David Potesil, Miroslava Sedlackova, Alena Salasova, Zachary Steinhart, Stephane Angers, Gunnar Schulte, Ales Hampl, Zbynek Zdrahal, Vitezslav Bryja^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

56 Citations (Scopus)

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 amultitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunitassociated 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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue	33
Pages (from-to)	9304-9309
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1608783113
Publication status	Published - 16 Aug 2016
Externally published	Yes

Keywords

Centrosome
Dishevelled
Linker proteins
NEK2
Wnt signaling

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10.1073/pnas.1608783113

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Cervenka, I., Valnohova, J., Bernatik, O., Harnos, J., Radsetoulal, M., Sedova, K., Hanakova, K., Potesil, D., Sedlackova, M., Salasova, A., Steinhart, Z., Angers, S., Schulte, G., Hampl, A., Zdrahal, Z., & Bryja, V. (2016). Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins. Proceedings of the National Academy of Sciences of the United States of America, 113(33), 9304-9309. https://doi.org/10.1073/pnas.1608783113

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title = "Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins",

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 amultitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunitassociated 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 = "Centrosome, Dishevelled, Linker proteins, NEK2, Wnt signaling",

author = "Igor Cervenka and Jana Valnohova and Ondrej Bernatik and Jakub Harnos and Matej Radsetoulal and Katerina Sedova and Katerina Hanakova and David Potesil and Miroslava Sedlackova and Alena Salasova and Zachary Steinhart and Stephane Angers and Gunnar Schulte and Ales Hampl and Zbynek Zdrahal and Vitezslav Bryja",

year = "2016",

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doi = "10.1073/pnas.1608783113",

language = "English",

volume = "113",

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Cervenka, I, Valnohova, J, Bernatik, O, Harnos, J, Radsetoulal, M, Sedova, K, Hanakova, K, Potesil, D, Sedlackova, M, Salasova, A, Steinhart, Z, Angers, S, Schulte, G, Hampl, A, Zdrahal, Z & Bryja, V 2016, 'Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 33, pp. 9304-9309. https://doi.org/10.1073/pnas.1608783113

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins. / Cervenka, Igor; Valnohova, Jana; Bernatik, Ondrej et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 33, 16.08.2016, p. 9304-9309.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

AU - Cervenka, Igor

AU - Valnohova, Jana

AU - Bernatik, Ondrej

AU - Harnos, Jakub

AU - Radsetoulal, Matej

AU - Sedova, Katerina

AU - Hanakova, Katerina

AU - Potesil, David

AU - Sedlackova, Miroslava

AU - Salasova, Alena

AU - Steinhart, Zachary

AU - Angers, Stephane

AU - Schulte, Gunnar

AU - Hampl, Ales

AU - Zdrahal, Zbynek

AU - Bryja, Vitezslav

PY - 2016/8/16

Y1 - 2016/8/16

N2 - 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 amultitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunitassociated 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.

AB - 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 amultitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunitassociated 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.

KW - Centrosome

KW - Dishevelled

KW - Linker proteins

KW - NEK2

KW - Wnt signaling

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U2 - 10.1073/pnas.1608783113

DO - 10.1073/pnas.1608783113

M3 - Journal article

C2 - 27486244

AN - SCOPUS:84982112080

SN - 0027-8424

VL - 113

SP - 9304

EP - 9309

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 33

ER -

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

Abstract

Keywords

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