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Phosphorylation regulates targeting of cytoplasmic dynein to kinetochores during mitosis

¹ Department of Biological Sciences and ² Notre Dame Integrated Imaging Facility, University of Notre Dame, Notre Dame, IN 46556
³ Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville, VA 22908
⁴ Harvard Microchemistry and Proteomics Facility, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138
⁵ Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta T6G1Z2, Canada

Correspondence to Kevin T. Vaughan: Vaughan.4{at}nd.edu

Cytoplasmic dynein functions at several sites during mitosis; however, the basis of targeting to each site remains unclear. Tandem mass spectrometry analysis of mitotic dynein revealed a phosphorylation site in the dynein intermediate chains (ICs) that mediates binding to kinetochores. IC phosphorylation directs binding to zw10 rather than dynactin, and this interaction is needed for kinetochore dynein localization. Phosphodynein associates with kinetochores from nuclear envelope breakdown to metaphase, but bioriented microtubule (MT) attachment and chromosome alignment induce IC dephosphorylation. IC dephosphorylation stimulates binding to dynactin and poleward streaming. MT depolymerization, release of kinetochore tension, and a PP1- mutant each inhibited IC dephosphorylation, leading to the retention of phosphodynein at kinetochores and reduced poleward streaming. The depletion of kinetochore dynactin by moderate levels of p50(dynamitin) expression disrupted the ability of dynein to remove checkpoint proteins by streaming at metaphase but not other aspects of kinetochore dynein activity. Together, these results suggest a new model for localization of kinetochore dynein and the contribution of kinetochore dynactin.

Abbreviations used in this paper: ACA, autoimmune chromosomal antigen; CSF, cytostatic factor; IC, intermediate chain; IFM, immunofluorescence microscopy; LIC, light IC; MS, mass spectrometry; MT, microtubule; SAC, spindle assembly checkpoint; shRNA, short hairpin RNA.

© 2008 Whyte et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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Dynein gives the "all clear"

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• Chan, Y. W., Fava, L. L., Uldschmid, A., Schmitz, M. H.A., Gerlich, D. W., Nigg, E. A., Santamaria, A. (2009). Mitotic control of kinetochore-associated dynein and spindle orientation by human Spindly. JCB 185: 859-874 [Abstract] [Full Text]  
• Sedwick, C. (2008). Dynein gives the "all clear". JCB 183: 753-753 [Full Text]  

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