title: GSK3-mediated CLASP2 phosphorylation modulates kinetochore dynamics.
abstract: Error-free chromosome segregation requires dynamic control of microtubule attachment to kinetochores, but how kinetochore-microtubule interactions are spatially and temporally controlled during mitosis remains incompletely understood. In addition to the NDC80 microtubule-binding complex, other proteins with demonstrated microtubule-binding activities localize to kinetochores. One such protein is the cytoplasmic linker-associated protein 2 (CLASP2). Here, we show that global GSK3-mediated phosphorylation of the longest isoform, CLASP2α, largely abolishes CLASP2α-microtubule association in metaphase. However, it does not directly control localization of CLASP2α to kinetochores. Using dominant phosphorylation-site variants, we find that CLASP2α phosphorylation weakens kinetochore-microtubule interactions as evidenced by decreased tension between sister kinetochores. Expression of CLASP2α phosphorylation-site mutants also resulted in increased chromosome segregation defects, indicating that GSK3-mediated control of CLASP2α-microtubule interactions contributes to correct chromosome dynamics. Because of global inhibition of CLASP2α-microtubule interactions, we propose a model in which only kinetochore-bound CLASP2α is dephosphorylated, locally engaging its microtubule-binding activity.
authors.affiliation: Department of Cell & Tissue Biology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Hayley
authors.initials: H
authors.lastname: Pemble
authors.affiliation: Department of Cell & Tissue Biology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Cell & Tissue Biology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: van Haren
authors.affiliation: Department of Cell & Tissue Biology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA torsten.wittmann@ucsf.edu.
authors.forename: Torsten
authors.identifier: 0000-0001-9134-691X
authors.initials: T
authors.lastname: Wittmann
mesh_terms: D016203:CDC2 Protein Kinase; D002460:Cell Line; D020090:Chromosome Segregation / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D018386:Kinetochores / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding; D015202:Protein Engineering
chemical_list: C497851:CLASP2 protein, human; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; C120529:NDC80 protein, human; D009687:Nuclear Proteins; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3
keywords: CLASP2; GSK3; Kinetochore; Microtubule; Mitosis; Phosphorylation