title: Cdk1 phosphorylates the Rac activator Tiam1 to activate centrosomal Pak and promote mitotic spindle formation.
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.
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Whalley
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Porter
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Diamantopoulou
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Gavin R M
authors.initials: GR
authors.lastname: White
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Castañeda-Saucedo
authors.affiliation: Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Malliri
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004285:Dogs; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D010766:Phosphorylation; D008941:Spindle Apparatus / Q000378:metabolism*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020744:rac GTP-Binding Proteins
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C470243:KIF11 protein, human; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D016547:Kinesins; D020744:rac GTP-Binding Proteins