Martha Cyert, Postdoctoral Faculty Sponsor
Kinetochore phosphatases suppress autonomous Polo-like kinase 1 activity to control the mitotic checkpoint
JOURNAL OF CELL BIOLOGY
2020; 219 (12)
Local phosphatase regulation is needed at kinetochores to silence the mitotic checkpoint (a.k.a. spindle assembly checkpoint [SAC]). A key event in this regard is the dephosphorylation of MELT repeats on KNL1, which removes SAC proteins from the kinetochore, including the BUB complex. We show here that PP1 and PP2A-B56 phosphatases are primarily required to remove Polo-like kinase 1 (PLK1) from the BUB complex, which can otherwise maintain MELT phosphorylation in an autocatalytic manner. This appears to be their principal role in the SAC because both phosphatases become redundant if PLK1 is inhibited or BUB-PLK1 interaction is prevented. Surprisingly, MELT dephosphorylation can occur normally under these conditions even when the levels or activities of PP1 and PP2A are strongly inhibited at kinetochores. Therefore, these data imply that kinetochore phosphatase regulation is critical for the SAC, but primarily to restrain and extinguish autonomous PLK1 activity. This is likely a conserved feature of the metazoan SAC, since the relevant PLK1 and PP2A-B56 binding motifs have coevolved in the same region on MADBUB homologues.
View details for DOI 10.1083/jcb.202002020
View details for Web of Science ID 000607623100007
View details for PubMedID 33125045
View details for PubMedCentralID PMC7608062
PP1 and PP2A Use Opposite Phospho-dependencies to Control Distinct Processes at the Kinetochore
2019; 28 (8): 2206-+
PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated.
View details for DOI 10.1016/j.celrep.2019.07.067
View details for Web of Science ID 000482135400021
View details for PubMedID 31433993
View details for PubMedCentralID PMC6715587
A fine balancing act: A delicate kinase-phosphatase equilibrium that protects against chromosomal instability and cancer
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
2018; 96: 148-156
Cancer cells rewire signalling networks to acquire specific hallmarks needed for their proliferation, survival, and dissemination throughout the body. Although this is often associated with the constitutive activation or inactivation of protein phosphorylation networks, there are other contexts when the dysregulation must be much milder. For example, chromosomal instability is a widespread cancer hallmark that relies on subtle defects in chromosome replication and/or division, such that these processes remain functional, but nevertheless error-prone. In this article, we will discuss how perturbations to the delicate kinase-phosphatase balance could lie at the heart of this type of dysregulation. In particular, we will explain how the two principle mechanisms that safeguard the chromosome segregation process rely on an equilibrium between at least two kinases and two phosphatases to function correctly. This balance is set during mitosis by a central complex that has also been implicated in chromosomal instability - the BUB1/BUBR1/BUB3 complex - and we will put forward a hypothesis that could link these two findings. This could be relevant for cancer treatment because most tumours have evolved by pushing the boundaries of chromosomal instability to the limit. If this involves subtle changes to the kinase-phosphatase equilibrium, then it may be possible to exacerbate these defects and tip tumour cells over the edge, whilst still maintaining the viability of healthy cells.
View details for DOI 10.1016/j.biocel.2017.10.017
View details for Web of Science ID 000426232200013
View details for PubMedID 29108876