A Reaction-Diffusion Model of the Centromere-Signaling Network

The centromere-signaling network (CSN) consists of two positive feedback loops that create a biaxial coordinate system of phosphorylated histones across mitotic chromosomes. This system localizes chromosomal passenger complex (CPC) to the inner centromere, which allows its protein kinase constituent, Aurora B, to correct errors in chromosome segregation that occur in 40% of cancers. Although the CSN has been experimentally derived, the requirements of the positive feedback loops have not been examined mathematically. To gain a better understanding of the mechanisms and properties of CPC accumulation, we curated a reaction-diffusion model to capture the emergent phenomena of the CSN. The model, which included both temporal and spatial information, demonstrated the importance of a strong but balanced response between the two positive feedback loops for CPC enrichment. The proteins, Haspin, NDC80, and KNL1, were found to be essential toward this aspect of the model. Furthermore, we performed a sensitivity analysis to identify parameters that have the greatest effect on CPC enrichment. Our analysis suggests that Bub1, CPC, and Sgo1 are key modulators of the pathway while histones have little effect. This information is valuable in generating hypotheses for further experimentation and in identifying targets for drug treatment. Furthermore, the model provided evidence that the CSN alone is sufficient for significant CPC accumulation in the inner centromere.