Abstract
Regulated interactions between kinetochores and spindle microtubules are essential to maintain genomic stability during chromosome segregation. The Aurora B kinase phosphorylates kinetochore substrates to destabilize kinetochore–microtubule interactions and eliminate incorrect attachments. These substrates must be dephosphorylated to stabilize correct attachments, but how opposing kinase and phosphatase activities are coordinated at the kinetochore is unknown. Here, we demonstrate that a conserved motif in the kinetochore protein KNL1 directly interacts with and targets protein phosphatase 1 (PP1) to the outer kinetochore. PP1 recruitment by KNL1 is required to dephosphorylate Aurora B substrates at kinetochores and stabilize microtubule attachments. PP1 levels at kinetochores are regulated and inversely proportional to local Aurora B activity. Indeed, we demonstrate that phosphorylation of KNL1 by Aurora B disrupts the KNL1–PP1 interaction. In total, our results support a positive feedback mechanism by which Aurora B activity at kinetochores not only targets substrates directly, but also prevents localization of the opposing phosphatase.
References
47
Referenced
332
10.1016/S0960-9822(00)00673-4
/ Curr. Biol. / INCENP binds the Aurora-related kinase AIRK2 and is required to target it to chromosomes, the central spindle and cleavage furrow by Adams (2000)10.1101/gad.1865909
/ Genes Dev. / Quantitative proteomic analysis of purified yeast kinetochores identifies a PP1 regulatory subunit by Akiyoshi (2009)10.1016/S1534-5807(04)00025-5
/ Dev. Cell. / Aurora B regulates MCAK at the mitotic centromere by Andrews (2004)10.1016/j.tcb.2009.06.005
/ Trends Cell Biol. / Mitotic phosphatases: from entry guards to exit guides by Bollen (2009)10.1021/ac0618730
/ Anal. Chem. / Optimizing TiO2-based phosphopeptide enrichment for automated multidimensional liquid chromatography coupled to tandem mass spectrometry by Cantin (2007)10.1016/j.ceb.2009.09.008
/ Curr. Opin. Cell Biol. / Making the Auroras glow: regulation of Aurora A and B kinase function by interacting proteins by Carmena (2009)10.1126/stke.2662005pl1
/ Sci. STKE. / A combined approach for the localization and tandem affinity purification of protein complexes from metazoans by Cheeseman (2005)10.1038/nrm2310
/ Nat. Rev. Mol. Cell Biol. / Molecular architecture of the kinetochore-microtubule interface by Cheeseman (2008)10.1016/S0092-8674(02)00973-X
/ Cell. / Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p by Cheeseman (2002)10.1101/gad.1234104
/ Genes Dev. / A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension by Cheeseman (2004)10.1016/j.cell.2006.09.039
/ Cell. / The conserved KMN network constitutes the core microtubule-binding site of the kinetochore by Cheeseman (2006)10.1091/mbc.E07-10-1051
/ Mol. Biol. Cell. / KNL1 and the CENP-H/I/K complex coordinately direct kinetochore assembly in vertebrates by Cheeseman (2008)10.1016/j.cell.2008.03.020
/ Cell. / Implications for kinetochore-microtubule attachment from the structure of an engineered Ndc80 complex by Ciferri (2008)10.1242/jcs.115.2.241
/ J. Cell Sci. / Protein phosphatase 1—targeted in many directions by Cohen (2002)10.1016/j.cell.2006.09.047
/ Cell. / Kinetochore microtubule dynamics and attachment stability are regulated by Hec1 by DeLuca (2006)10.1016/j.ceb.2009.08.003
/ Curr. Opin. Cell Biol. / Protein phosphatases take the mitotic stage by De Wulf (2009)10.1101/gad.1126303
/ Genes Dev. / KNL-1 directs assembly of the microtubule-binding interface of the kinetochore in C. elegans by Desai (2003)10.1093/emboj/16.8.1876
/ EMBO J. / Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1 by Egloff (1997)10.1083/jcb.200710019
/ J. Cell Biol. / Aurora B kinase and protein phosphatase 1 have opposing roles in modulating kinetochore assembly by Emanuele (2008){'key': '2023072905251228400_bib20', 'first-page': '4731', 'article-title': 'Type 1 protein phosphatase acts in opposition to IpL1 protein kinase in regulating yeast chromosome segregation', 'volume': '14', 'author': 'Francisco', 'year': '1994', 'journal-title': 'Mol. Cell. Biol.'}
/ Mol. Cell. Biol. / Type 1 protein phosphatase acts in opposition to IpL1 protein kinase in regulating yeast chromosome segregation by Francisco (1994)10.1038/nature06923
/ Nature. / Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient by Fuller (2008)10.1038/ncb1702
/ Nat. Cell Biol. / Phosphoregulation and depolymerization-driven movement of the Dam1 complex do not require ring formation by Gestaut (2008)10.1016/j.cub.2008.08.012
/ Curr. Biol. / Kinetochore-microtubule attachment relies on the disordered N-terminal tail domain of Hec1 by Guimaraes (2008)10.1016/j.chembiol.2009.02.012
/ Chem. Biol. / Docking motif-guided mapping of the interactome of protein phosphatase-1 by Hendrickx (2009)10.1242/jcs.00645
/ J. Cell Sci. / Dynamic behavior of Nuf2-Hec1 complex that localizes to the centrosome and centromere and is essential for mitotic progression in vertebrate cells by Hori (2003)10.1016/S0092-8674(00)00034-9
/ Cell. / Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes by Hsu (2000)10.1091/mbc.E04-06-0443
/ Mol. Biol. Cell. / The fission yeast kinetochore component Spc7 associates with the EB1 family member Mal3 and is required for kinetochore-spindle association by Kerres (2004)10.1242/jcs.113.21.3815
/ J. Cell Sci. / Tension on chromosomes increases the number of kinetochore microtubules but only within limits by King (2000)10.1016/j.devcel.2007.09.005
/ Dev. Cell. / Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1 by Kiyomitsu (2007)10.1038/ncb1102
/ Nat. Cell Biol. / Correcting improper chromosome-spindle attachments during cell division by Lampson (2004)10.1016/j.cub.2004.01.055
/ Curr. Biol. / Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity by Lan (2004)10.1126/science.1167000
/ Science. / Sensing chromosome bi-orientation by spatial separation of aurora B kinase from kinetochore substrates by Liu (2009)10.1038/nrm2163
/ Nat. Rev. Mol. Cell Biol. / The spindle-assembly checkpoint in space and time by Musacchio (2007)10.1091/mbc.E03-06-0419
/ Mol. Biol. Cell. / Interactions between centromere complexes in Saccharomyces cerevisiae by Nekrasov (2003)10.1091/mbc.E04-02-0082
/ Mol. Biol. Cell. / Differentiation of cytoplasmic and meiotic spindle assembly MCAK functions by Aurora B-dependent phosphorylation by Ohi (2004)10.1038/ncb1396
/ Nat. Cell Biol. / The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres by Okada (2006)10.1128/MCB.26.7.2648-2660.2006
/ Mol. Cell. Biol. / Glc7/protein phosphatase 1 regulatory subunits can oppose the Ipl1/aurora protein kinase by redistributing Glc7 by Pinsky (2006)10.1371/journal.pone.0000478
/ PLoS One. / Molecular analysis of core kinetochore composition and assembly in Drosophila melanogaster by Przewloka (2007)10.1038/nrm2257
/ Nat. Rev. Mol. Cell Biol. / Chromosomal passengers: conducting cell division by Ruchaud (2007)10.1038/emboj.2009.173
/ EMBO J. / The life and miracles of kinetochores by Santaguida (2009)10.1016/S0955-0674(02)00328-9
/ Curr. Opin. Cell Biol. / Bi-orienting chromosomes on the mitotic spindle by Tanaka (2002)10.1016/j.ceb.2006.09.001
/ Curr. Opin. Cell Biol. / Mitotic phosphatases: no longer silent partners by Trinkle-Mulcahy (2006)10.1091/mbc.E02-07-0376
/ Mol. Biol. Cell. / Time-lapse imaging reveals dynamic relocalization of PP1gamma throughout the mammalian cell cycle by Trinkle-Mulcahy (2003)10.1083/jcb.200508154
/ J. Cell Biol. / Repo-Man recruits PP1γ to chromatin and is essential for cell viability by Trinkle-Mulcahy (2006)10.1016/j.cub.2009.05.060
/ Curr. Biol. / A novel protein phosphatase 1-dependent spindle checkpoint silencing mechanism by Vanoosthuyse (2009)10.1038/85686
/ Nat. Biotechnol. / Large-scale analysis of the yeast proteome by multidimensional protein identification technology by Washburn (2001)10.1016/j.molcel.2010.02.034
/ Mol. Cell. / Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface by Welburn (2010)
Dates
Type | When |
---|---|
Created | 15 years, 5 months ago (March 15, 2010, 11:54 p.m.) |
Deposited | 2 years ago (July 29, 2023, 1:25 a.m.) |
Indexed | 3 days, 2 hours ago (Aug. 23, 2025, 9:49 p.m.) |
Issued | 15 years, 5 months ago (March 15, 2010) |
Published | 15 years, 5 months ago (March 15, 2010) |
Published Online | 15 years, 5 months ago (March 15, 2010) |
Published Print | 15 years, 5 months ago (March 22, 2010) |
@article{Liu_2010, title={Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase}, volume={188}, ISSN={0021-9525}, url={http://dx.doi.org/10.1083/jcb.201001006}, DOI={10.1083/jcb.201001006}, number={6}, journal={Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Liu, Dan and Vleugel, Mathijs and Backer, Chelsea B. and Hori, Tetsuya and Fukagawa, Tatsuo and Cheeseman, Iain M. and Lampson, Michael A.}, year={2010}, month=mar, pages={809–820} }