Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation.
| dc.contributor.author | Whalley, Helen J | |
| dc.contributor.author | Porter, Andrew P | |
| dc.contributor.author | Diamantopoulou, Zoi | |
| dc.contributor.author | White, Gavin R M | |
| dc.contributor.author | Castañeda-Saucedo, Eduardo | |
| dc.contributor.author | Malliri, Angeliki | |
| dc.date.accessioned | 2015-07-30T08:57:26Z | en |
| dc.date.available | 2015-07-30T08:57:26Z | en |
| dc.date.issued | 2015 | en |
| dc.identifier.citation | Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation. 2015, 6:7437 Nat Commun | en |
| dc.identifier.issn | 2041-1723 | en |
| dc.identifier.pmid | 26078008 | en |
| dc.identifier.doi | 10.1038/ncomms8437 | en |
| dc.identifier.uri | http://hdl.handle.net/10541/561224 | en |
| dc.description.abstract | Centrosome separation is critical for bipolar spindle formation and the accurate segregation of chromosomes during mammalian cell mitosis. Kinesin-5 (Eg5) is a microtubule motor essential for centrosome separation, and Tiam1 and its substrate Rac antagonize Eg5-dependent centrosome separation in early mitosis promoting efficient chromosome congression. Here we identify S1466 of Tiam1 as a novel Cdk1 site whose phosphorylation is required for the mitotic function of Tiam1. We find that this phosphorylation of Tiam1 is required for the activation of group I p21-activated kinases (Paks) on centrosomes in prophase. Further, we show that both Pak1 and Pak2 counteract centrosome separation in a kinase-dependent manner and demonstrate that they act downstream of Tiam1. We also show that depletion of Pak1/2 allows cells to escape monopolar arrest by Eg5 inhibition, highlighting the potential importance of this signalling pathway for the development of Eg5 inhibitors as cancer therapeutics. | |
| dc.language.iso | en | en |
| dc.rights | Archived with thanks to Nature communications | en |
| dc.title | Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation. | en |
| dc.type | Article | en |
| dc.contributor.department | Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK | en |
| dc.identifier.journal | Nature Communications | en |
| html.description.abstract | Centrosome separation is critical for bipolar spindle formation and the accurate segregation of chromosomes during mammalian cell mitosis. Kinesin-5 (Eg5) is a microtubule motor essential for centrosome separation, and Tiam1 and its substrate Rac antagonize Eg5-dependent centrosome separation in early mitosis promoting efficient chromosome congression. Here we identify S1466 of Tiam1 as a novel Cdk1 site whose phosphorylation is required for the mitotic function of Tiam1. We find that this phosphorylation of Tiam1 is required for the activation of group I p21-activated kinases (Paks) on centrosomes in prophase. Further, we show that both Pak1 and Pak2 counteract centrosome separation in a kinase-dependent manner and demonstrate that they act downstream of Tiam1. We also show that depletion of Pak1/2 allows cells to escape monopolar arrest by Eg5 inhibition, highlighting the potential importance of this signalling pathway for the development of Eg5 inhibitors as cancer therapeutics. |