PP1 and PP2A Use Opposite Phospho-dependencies to Control Distinct Processes at the Kinetochore

Abstract

Highlights d PP1 and PP2A-B56 can functionally substitute for each other at the kinetochore d The major difference is their ability to respond to phosphoinputs in opposite ways d This underlies their distinct phenotypic behaviors d Many other signaling pathways also select for these same key features

Hec1/Ndc80 Tail Domain Function at the Kinetochore-Microtubule Interface

“…Consistent with these findings, cells expressing a mutant version of BubR1 that is unable to recruit PP2A-B56 to kinetochores exhibit increased levels of phosphorylated Hec1 (at serine 55) (Smith et al, 2019). Interestingly, the authors of this study found that they could rescue PP1 and PP2A-B56 depletion phenotypes by artificially recruiting the other phosphatase to kinetochores, suggesting that the phosphatases may have little intrinsic site specificity (Smith et al, 2019). PP1 and PP2A-B56 are recruited to kinetochores at different times during mitosis -PP2A-B56 in early mitosis, and PP1 in late mitosis -therefore, it is possible that the timing of their recruitment underlies their substrate specificity.…”

“…Although one study in human cells reported a similar finding -that preventing PP1 recruitment to KNL1 compromises kinetochore-microtubule attachments (Liu et al, 2010) -two recent studies found that kinetochore-microtubule attachments and chromosome alignment were both largely unperturbed upon disruption of the PP1-KNL1 interaction (Shrestha et al, 2017;Smith et al, 2019). Consistent with these latter results, Smith et al (2019) reported no change in phosphorylation of Hec1 (on serine 55) at kinetochores in cells in which PP1-KNL1 recruitment was perturbed. These results suggest that dephosphorylation of the Hec1 tail domain by PP1 may not be a major effector of kinetochore-microtubule attachment regulation.…”

“…In C. elegans, preventing PP1 recruitment to its docking site on the kinetochore protein KNL1 delayed formation of loadbearing kinetochore-microtubule attachments; however, cells exhibited no obvious defects in chromosome segregation (Espeut et al, 2012). Although one study in human cells reported a similar finding -that preventing PP1 recruitment to KNL1 compromises kinetochore-microtubule attachments (Liu et al, 2010) -two recent studies found that kinetochore-microtubule attachments and chromosome alignment were both largely unperturbed upon disruption of the PP1-KNL1 interaction (Shrestha et al, 2017;Smith et al, 2019). Consistent with these latter results, Smith et al (2019) reported no change in phosphorylation of Hec1 (on serine 55) at kinetochores in cells in which PP1-KNL1 recruitment was perturbed.…”

“…The other major phosphatase implicated in regulating kinetochore-microtubule attachment stability is PP2A-B56, which is recruited to kinetochores by the spindle assembly checkpoint effector BubR1 (Suijkerbuijk et al, 2012;Kruse et al, 2013;Xu et al, 2013). In contrast to PP1, inhibiting PP2A-B56 kinetochore recruitment leads to severe defects in chromosome alignment and kinetochore-microtubule attachments (Suijkerbuijk et al, 2012;Kruse et al, 2013;Xu et al, 2013;Shrestha et al, 2017;Smith et al, 2019). Consistent with these findings, cells expressing a mutant version of BubR1 that is unable to recruit PP2A-B56 to kinetochores exhibit increased levels of phosphorylated Hec1 (at serine 55) (Smith et al, 2019).…”

“…In contrast to PP1, inhibiting PP2A-B56 kinetochore recruitment leads to severe defects in chromosome alignment and kinetochore-microtubule attachments (Suijkerbuijk et al, 2012;Kruse et al, 2013;Xu et al, 2013;Shrestha et al, 2017;Smith et al, 2019). Consistent with these findings, cells expressing a mutant version of BubR1 that is unable to recruit PP2A-B56 to kinetochores exhibit increased levels of phosphorylated Hec1 (at serine 55) (Smith et al, 2019). Interestingly, the authors of this study found that they could rescue PP1 and PP2A-B56 depletion phenotypes by artificially recruiting the other phosphatase to kinetochores, suggesting that the phosphatases may have little intrinsic site specificity (Smith et al, 2019).…”