Abstract
SummaryTemporal control over protein phosphorylation and dephosphorylation is crucial for accurate chromosome segregation and for completion of the cell division cycle during exit from mitosis. In budding yeast, the Cdc14 phosphatase is thought to be a major regulator at this time, while in higher eukaryotes PP2A phosphatases take a dominant role. Here, we use time-resolved phosphoproteome analysis in budding yeast to evaluate the respective contributions of Cdc14, PP2ACdc55, and PP2ARts1. This reveals an overlapping requirement for all three phosphatases during mitotic progression. Our time-resolved phosphoproteome resource reveals how Cdc14 instructs the sequential pattern of phosphorylation changes, in part through preferential recognition of serine-based cyclin-dependent kinase (Cdk) substrates. PP2ACdc55 and PP2ARts1 in turn exhibit a broad substrate spectrum with some selectivity for phosphothreonines and a role for PP2ARts1 in sustaining Aurora kinase activity. These results illustrate synergy and coordination between phosphatases as they orchestrate phosphoproteome dynamics during mitotic progression.
Highlights
Cell-cycle progression is driven by waves of protein phosphorylation and dephosphorylation, mediated by the interplay of cellcycle kinases and phosphatases (Gelens et al, 2018; Morgan, 2007; Uhlmann et al, 2011)
The focus of this study lies on the progression through mitosis, when metaphase, anaphase, and cytokinesis have to occur in strict order to avoid cell division failure and consequent aneuploidy
‘‘nuclear Dbf2-related’’ (NDR) kinases Mob1-Dbf2 and Mob2-Cbk1 are activated as cyclin-dependent kinase (Cdk) activity decreases, thereby promoting late mitosis-specific phosphorylation events that contribute to chromosome segregation and cytokinesis (Afonso et al, 2017; Botchkarev and Haber, 2018; Tamborrini et al, 2018; Weiss, 2012)
Summary
Cell-cycle progression is driven by waves of protein phosphorylation and dephosphorylation, mediated by the interplay of cellcycle kinases and phosphatases (Gelens et al, 2018; Morgan, 2007; Uhlmann et al, 2011). Together with cyclic protein synthesis and degradation, these waves order the sequential events during cell growth and division. The focus of this study lies on the progression through mitosis, when metaphase, anaphase, and cytokinesis have to occur in strict order to avoid cell division failure and consequent aneuploidy. Over 300 proteins are regulated by phosphorylation and dephosphorylation during this time (Touati et al, 2018). Levels of the master cyclin-dependent kinase (Cdk) peak in metaphase, after which anaphase-promoting complex (APC)-mediated cyclin proteolysis initiates downregulation of Cdk activity. ‘‘nuclear Dbf2-related’’ (NDR) kinases Mob1-Dbf and Mob2-Cbk are activated as Cdk activity decreases, thereby promoting late mitosis-specific phosphorylation events that contribute to chromosome segregation and cytokinesis (Afonso et al, 2017; Botchkarev and Haber, 2018; Tamborrini et al, 2018; Weiss, 2012)
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