Kinetochore-localized PP1–Sds22 couples chromosome segregation to polar relaxation

Abstract

Cell division requires the precise coordination of chromosome segregation and cytokinesis. This coordination is achieved by the recruitment of an actomyosin regulator, Ect2, to overlapping microtubules at the centre of the elongating anaphase spindle. Ect2 then signals to the overlying cortex to promote the assembly and constriction of an actomyosin ring between segregating chromosomes. Here, by studying division in proliferating Drosophila and human cells, we demonstrate the existence of a second, parallel signalling pathway, which triggers the relaxation of the polar cell cortex at mid anaphase. This is independent of furrow formation, centrosomes and microtubules and, instead, depends on PP1 phosphatase and its regulatory subunit Sds22 (refs 2, 3). As separating chromosomes move towards the polar cortex at mid anaphase, kinetochore-localized PP1-Sds22 helps to break cortical symmetry by inducing the dephosphorylation and inactivation of ezrin/radixin/moesin proteins at cell poles. This promotes local softening of the cortex, facilitating anaphase elongation and orderly cell division. In summary, this identifies a conserved kinetochore-based phosphatase signal and substrate, which function together to link anaphase chromosome movements to cortical polarization, thereby coupling chromosome segregation to cell division.

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

“…It is noteworthy that PLK1-Sds22 interaction may also orchestrate the anaphase events, because perturbation of Sds22 resulted in aberrant polar relaxation and chromosome instability phenotypes (30,31). Because numerous studies argued that Sds22 remains on kinetochores throughout anaphase when PLK1 has relocated to central spindle and midzone, it would be of central importance to identify the elements responsible for Sds22 distribution at the kinetochore during chromosome segregation during cell division and the spatiotemporal dynamics of PP1-Sds22 interaction during kinetochore attachment error correction process.…”

“…Upon cellular depletion of Sds22, Aurora B autophosphorylation at Thr 232 in the activation loop and unbalanced Aurora B activity is increased during establishment of bipolar attachment (23). During anaphase, Sds22 is required to stabilize kinetochorespindle attachment (30,31). However, whether Sds22 localizes to kinetochores remains elusive (7,32).…”

Roles of actin binding proteins in mammalian oocyte maturation and beyond

“…77 Recently, kinetochore-localized protein phosphatase 1 (PP1)-SDS22 holoenzymes were shown to dephosphorylate p-ERM in the cell cortex and break cortical symmetry. 124 It is not clear whether PP1-SDS22 is responsible for p-ERM exclusion in the region of the cortical actin cap in oocytes, and further studies are needed to validate these results. However, because the PP1 targeting subunit SDS22 contains a predicted leucinerich repeat domain, which is frequently found in many RANbinding proteins including RANGAPs, 125 this finding suggests the possibility that the protein phosphatase activity of SDS22-PP1 is regulated by the RAN GTP gradient.…”

Coupling changes in cell shape to chromosome segregation

“…In previous decades, this type of activity was often attributed to the ability of the growing, plus ends of astral microtubules to induce cortical softening at cell poles 108 . Although the complex ity of microtubulebased signals are yet to be resolved (for example, furrow components accumulate at the tips of microtubules in the absence of micro tubule overlap in cells exiting mitosis with a monopolar spindle 109,110 ), it is now clear that the anaphase spindle 106,[111][112][113] also signals to the cortex via microtubuleindependent sig nals. In support of this, polar relaxation still occurs near anaphase chromatin in cells that lack spindle poles and/or microtubules 106 .…”

“…106) to cell poles is accom panied by PP1-SDS22dependent dephosphorylation of ERM proteins 51,52,81 and the loss of polar actomyo sin 118 , before the accumulation of actomyosin at the cell midzone. As PP1 promotes the largescale reversal of mitotic phosphorylation at mitotic exit 119 , potentially aiding inactivation of the spindle checkpoint 120 , the rise in PP1 activity at anaphase effectively couples cortical mechanics (that lead to the shape changes) to the change in mitotic state.…”