Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms8437
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Funding
- MRC [MR/J00104X/1] Funding Source: UKRI
- Cancer Research UK [20410] Funding Source: researchfish
- Medical Research Council [MR/J00104X/1] Funding Source: researchfish
- Worldwide Cancer Research [12-0037] Funding Source: researchfish
- Cancer Research UK [A12937, C5759/A12328] Funding Source: Medline
- Medical Research Council [MR/J00104X/1] Funding Source: Medline
- Worldwide Cancer Research [12-0037] Funding Source: Medline
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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.
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