Abstract
ABSTRACTEntry 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.
Highlights
The phosphorylation of proteins by cyclin-dependent kinase 1 (Cdk1) is essential for correct entry into, and progression through, mitosis (Lindqvist et al, 2009)
Securin was rapidly degraded within 5 min, whereas cyclin B1 was slowly degraded throughout the timecourse, reaching interphase levels at approximately 60–90 min post Cdk1 inhibition, indicating that cells had completed mitotic exit by this time (Fig. 1B)
We propose that PP1 initiates the dephosphorylation of microtubule-associated serine-threonine-like kinase (MASTL), relieving the inhibition of PP2A, which completes the full deactivation of MASTL
Summary
The phosphorylation of proteins by cyclin-dependent kinase 1 (Cdk1) is essential for correct entry into, and progression through, mitosis (Lindqvist et al, 2009). This process is monitored by the spindle assembly checkpoint (SAC), which ensures that Cdk remains active until all chromosomes are correctly attached and aligned Once this is achieved, the SAC becomes satisfied, releasing inhibition of the E3 ubiquitin ligase. Oscillating activities of Cdk and phosphatase enzymes create a two-state system, which comprises interphase and mitosis, respectively (Medema and Lindqvist, 2011). This bistability has been extensively modelled mathematically, especially with regards to the role of Cdk and to protein degradation during mitotic exit (López-Avilés et al, 2009; Rattani et al, 2014; Tóth et al, 2007). How regulation of Cdk activity ensures the irreversibility of mitotic exit is well established
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
