PP1 initiates the dephosphorylation of MASTL, triggering mitotic exit and bistability in human cells

Rogers, Samuel; Fey, Dirk; McCloy, Rachael A.; Parker, Benjamin L.; Mitchell, Nicholas J.; Payne, Richard J.; Daly, Roger J.; James, David E.; Caldon, C. Elizabeth; Watkins, D. Neil; Croucher, David R.; Burgess, Andrew

Abstract

Entry into mitosis is driven by the phosphorylation of thousands of substrates, under the master control of Cdk1. During entry into mitosis, Cdk1, in collaboration with MASTL kinase, represses the activity of the major mitotic protein phosphatases, PP1 and PP2A, thereby ensuring mitotic substrates remain phosphorylated. For cells to complete and exit mitosis, these phosphorylation events must be removed, and hence, phosphatase activity must be reactivated. This reactivation of phosphatase activity presumably requires the inhibition of MASTL; however, it is not currently understood what deactivates MASTL and how this is achieved. In this study, we identified that PP1 is associated with, and capable of partially dephosphorylating and deactivating, MASTL during mitotic exit. Using mathematical modelling, we were able to confirm that deactivation of MASTL is essential for mitotic exit. Furthermore, small decreases in Cdk1 activity during metaphase are sufficient to initiate the reactivation of PP1, which in turn partially deactivates MASTL to release inhibition of PP2A and, hence, create a feedback loop. This feedback loop drives complete deactivation of MASTL, ensuring a strong switch-like activation of phosphatase activity during mitotic exit.

Citation

Rogers, S., Fey, D., McCloy, R. A., Parker, B. L., Mitchell, N. J., Payne, R. J., Daly, R. J., James, D. E., Caldon, C. E., Watkins, D. N., Croucher, D. R., & Burgess, A. (2016). PP1 initiates the dephosphorylation of MASTL, triggering mitotic exit and bistability in human cells. Journal of Cell Science, 129(7), 1340-1354. https://doi.org/10.1242/jcs.179754

• Journal Article Type: Article
• Acceptance Date: Feb 8, 2016
• Online Publication Date: Feb 12, 2016
• Publication Date: Apr 1, 2016
• Deposit Date: Nov 20, 2018
• Publicly Available Date: Jan 22, 2019
• Journal: Journal of Cell Science
• Print ISSN: 0021-9533
• Electronic ISSN: 1477-9137
• Publisher: Company of Biologists
• Peer Reviewed: Peer Reviewed
• Volume: 129
• Issue: 7
• Pages: 1340-1354
• DOI: https://doi.org/10.1242/jcs.179754
• Keywords: Cell Biology
• Public URL: https://nottingham-repository.worktribe.com/output/1286826
• Publisher URL: http://jcs.biologists.org/content/129/7/1340
• Contract Date: Nov 20, 2018