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BIOLOGICAL SCIENCES / BIOPHYSICS
Modeling dual pathways for the metazoan spindle assembly checkpoint
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Department of Physics, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom; and Department of Mathematics, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
Edited by Michael Levitt, Stanford University School of Medicine, Stanford, CA, and approved September 11, 2006 (received for review April 19, 2006)
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 able to trigger anaphase onset even without support from the other pathway.
kinetochore | mathematical modeling | signal transduction | concentration gradients
The authors declare no conflict of interest.
This article is a PNAS direct submission.
To whom correspondence should be addressed. E-mail: martin.howard{at}imperial.ac.uk
© 2006 by The National Academy of Sciences of the USA
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