Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation

Helen J. Whalley, Andrew P. Porter, Zoi Diamantopoulou, Gavin R. M. White, Eduardo Castañeda-Saucedo and Angeliki Malliri ()
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Helen J. Whalley: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester
Andrew P. Porter: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester
Zoi Diamantopoulou: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester
Gavin R. M. White: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester
Eduardo Castañeda-Saucedo: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester
Angeliki Malliri: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8437

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