Modeling dual pathways for the metazoan spindle assembly checkpoint

Proceedings of the National Academy of Sciences of the United States of America
Richard P Sear, Martin Howard


Using computational modeling, we investigate mechanisms of signal transduction. We focus on the spindle assembly checkpoint, where a single unattached kinetochore is able to signal to prevent cell cycle progression. The inhibitory signal switches off rapidly once spindle microtubules have attached to all kinetochores. This requirement tightly constrains the possible mechanisms. Here we investigate two possible mechanisms for spindle checkpoint operation in metazoan cells, both supported by recent experiments. The first involves the free diffusion and sequestration of cell cycle regulators. This mechanism is severely constrained both by experimental fluorescence recovery data and by the large volumes involved in open mitosis in metazoan cells. By using a simple mathematical analysis and computer simulation, we find that this mechanism can generate the inhibition found in experiment but likely requires a two-stage signal amplification cascade. The second mechanism involves spatial gradients of a short-lived inhibitory signal that propagates first by diffusion but then primarily by active transport along spindle microtubules. We propose that both mechanisms may be operative in the metazoan spindle assembly checkpoint, with either ...Continue Reading


Jan 12, 2011·Journal of Mathematical Biology·Chris Levy, David Iron
Aug 10, 2010·Journal of Pharmacokinetics and Pharmacodynamics·Hiroko KameiFordyce A Davidson
Apr 12, 2007·Nature Reviews. Molecular Cell Biology·Andrea Musacchio, Edward D Salmon
Dec 19, 2008·Proceedings of the National Academy of Sciences of the United States of America·Hitesh B MistryFordyce A Davidson
Jan 16, 2009·PLoS Biology·Marco SimonettaAndrea Ciliberto
Feb 7, 2008·PloS One·Bashar IbrahimPeter Dittrich
Aug 5, 2009·PloS One·Andreas DoncicNaama Barkai
Oct 23, 2014·International Journal of Molecular Sciences·Bashar Ibrahim, Richard Henze
Feb 28, 2015·Progress in Biophysics and Molecular Biology·Bashar Ibrahim
Oct 21, 2015·Current Biology : CB·Andrea Musacchio
May 16, 2015·Computational and Structural Biotechnology Journal·Bashar Ibrahim
May 15, 2012·Molecular Systems Biology·Ayse Koca CaydasiBashar Ibrahim
May 8, 2016·Mathematical Biosciences·Kevin DohertyPetri T Piiroinen
May 14, 2016·Molecular Biology of the Cell·Pavithra AravamudhanAjit P Joglekar
Sep 13, 2014·Nature Communications·Jing Chen, Jian Liu
Sep 11, 2018·PLoS Computational Biology·Fridolin GrossAndrea Ciliberto
Jul 25, 2009·The EMBO Journal·Andrea Ciliberto, Jagesh V Shah
Jun 22, 2017·Scientific Reports·Richard HenzeBashar Ibrahim
May 22, 2020·PeerJ·Robert C Jackson, Hitesh B Mistry
Nov 23, 2017·Mathematical Biosciences and Engineering : MBE·Bashar Ibrahim
Jan 1, 2016·AIMS Molecular Science·Song-Tao Liu, Hang Zhang


Apr 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·S H Northrup, H P Erickson
Apr 1, 1986·The Journal of Cell Biology·I LangR Peters
Jul 1, 1981·Proceedings of the National Academy of Sciences of the United States of America·J W WojcieszynK A Jacobson
May 13, 1997·Proceedings of the National Academy of Sciences of the United States of America·C L RiederG Sluder
Jul 14, 1997·The Journal of Cell Biology·O SeksekA S Verkman
May 16, 1998·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·B F McEwenA B Heagle
Nov 13, 1999·Nature Cell Biology·P Clute, Jonathon Pines
Jun 7, 2002·Molecular Cell·Reinhart HeinrichTom A Rapoport
Oct 3, 2002·Nature Reviews. Molecular Cell Biology·Andrea Musacchio, Kevin G Hardwick
Dec 6, 2003·The EMBO Journal·Claudine KraftJan-Michael Peters
Apr 6, 2004·Molecular Biology of the Cell·Lars SchmiedebergPeter Hemmerich
Jun 9, 2004·Current Biology : CB·Bonnie J HowellEdward D Salmon
Jun 17, 2004·Genes & Development·Jing Pan, Rey-Huei Chen
Feb 8, 2005·Current Biology : CB·Anna De AntoniAndrea Musacchio
Mar 31, 2005·Cell·Kim Nasmyth
Apr 27, 2005·Proceedings of the National Academy of Sciences of the United States of America·Andreas DoncicNaama Barkai
May 18, 2005·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Anna DeAntoniAndrea Musacchio
Feb 17, 2006·Nature Reviews. Molecular Cell Biology·Boris N Kholodenko
Mar 10, 2006·The EMBO Journal·Marina MapelliAndrea Musacchio
Apr 25, 2006·Current Biology : CB·Martin VinkAndrea Musacchio

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