The accurate segregation of genetic material to daughter cells during mitosis depends on the precise coordination and regulation of hundreds of proteins by dynamic phosphorylation. Mitotic kinases are major regulators of protein function, but equally important are protein phosphatases that balance their actions, their coordinated activity being essential for accurate chromosome segregation. Phosphoprotein phosphatases (PPPs) that dephosphorylate phosphoserine and phosphothreonine residues are increasingly understood as essential regulators of mitosis. In contrast to kinases, the lack of a pronounced peptide-binding cleft on the catalytic subunit of PPPs suggests that these enzymes are unlikely to be specific. However, recent exciting insights into how mitotic PPPs recognize specific substrates have revealed that they are as specific as kinases. Furthermore, the activities of PPPs are tightly controlled at many levels to ensure that they are active only at the proper time and place. Here, I will discuss substrate selection and regulation of mitotic PPPs focusing mainly on animal cells and explore how these actions control mitosis, as well as important unanswered questions.

Dynamic phosphorylations control cell division

Mitosis is characterized by an ordered series of events in which first the nuclear envelope breaks down, chromosomes compact, and the mitotic spindle starts to assemble. Once the kinetochores on sister chromatids are attached to the mitotic spindle and properly bioriented, anaphase is initiated, and the sister chromatids separate and move to opposite poles of the dividing cell. This is followed by the reassembly of the nuclear envelope, decompaction of chromatin, cytokinesis, and finally, abscission that separates the two new daughter cells (Fig. 1 A). Because translation and transcription are suppressed during mitosis, the post-translational modification of proteins plays a prominent role in the orchestration of mitosis (Taylor, 1960; Prescott and Bender, 1962). Cdk1 in complex with cyclin B1 is the major mitotic kinase phosphorylating thousands of Ser-Pro (SP) and Thr-Pro (TP) sites to initiate and regulate mitosis (Olsen et al., 2010; Petrone et al., 2016). Cdk1 activity is controlled by the regulation of cyclin B1 stability, with cyclin B1 being degraded at metaphase by the anaphase-promoting complex/cyclosome (APC/C) in complex with Cdc20 (Pines, 2011). APC/C-Cdc20 activity is inhibited by the spindle assembly checkpoint (SAC) such that APC/C-Cdc20 becomes active only once all microtubules have properly attached to the kinetochores (Lara-Gonzalez et al., 2012). In addition to Cdk1-cyclin B1, many other mitotic kinases, including Plk1, Mps1, Bub1, Haspin, and the Aurora kinases, regulate cell division (Kettenbach et al., 2011; Santamaria et al., 2011). These kinases have unique localization patterns and phosphorylate distinct, specific sites on target proteins. However, kinases alone are insufficient to control dynamic processes such as mitosis because the phosphorylation of serine and threonine residues is extremely stable, with the half-life likely being longer than the lifetime of our planet (Lad et al., 2003). Therefore, protein phosphatases ensure that phosphorylations are dynamic and responsive. This is illustrated by the fact that cells are unable to exit mitosis when Cdk1 is inhibited if protein phosphatase activity is blocked (Skoufias et al., 2007). Because there are roughly 10 times more serine/threonine kinases encoded in the genome compared with serine/threonine phosphatases (Manning et al., 2002; Moorhead et al., 2007; Chen et al., 2017), this raises the question of how this limited number of phosphatases can balance the activities of all the kinases. As will be discussed, the solution to this problem is the dynamic assembly of phosphatase catalytic subunits into multiple different holoenzymes that target distinct substrates.

Phosphoprotein phosphatases (PPPs) regulating mitosis

Genetic screens, as well as cell-based and biochemical assays, have revealed that members of the PPPs namely PP1, PP2A, and PP6 holoenzymes, are important and essential regulators of mitosis in many model organisms (Ohkura et al., 1988; Booher and Beach, 1989; Doonan and Morris, 1989; Kinoshita et al., 1990; Mayer-Jaekel et al., 1993; Goshima et al., 2003; Chen et al., 2007; Afshar et al., 2010; Manchado et al., 2010; Schmitz et al., 2010; Zeng et al., 2010; Wurzenberger et al., 2012). In addition, Cdc25 phosphatases control mitotic entry, and Cdc14 is the major mitotic exit phosphatase in budding yeast (Stegmeier and Amon, 2004; Boutros et al., 2006; Clifford et al., 2008; Lindqvist et al., 2009). This function of Cdc14 is not conserved, and instead, PPP members are important regulators of mitotic exit in many other organisms. The focus of this review will be on PP1, PP2A, and PP6 because they are well-established regulators of mitosis, but it should be pointed out that Calcineurin (PP2B) is an important regulator of meiosis (Mochida and Hunt, 2007).

PP1 isoforms regulating mitosis

At first glance, PP1 appears to be the simplest mitotic phosphatase in that it consists of only a catalytic subunit (Fig. 2 A). However, PP1 likely never exists in an unbound form but assembles into hundreds of different holoenzyme complexes that each have distinct substrate-binding domains and localization patterns (Moorhead et al., 2008; Hendrickx et al., 2009; Heroes et al., 2013; Choy et al., 2014). The three human isoforms of PP1 (PPP1CA-C, PP1α-γ; there are two splice variants of PP1γ: PP1γ1 and PP1γ2, with PP1γ1 often referred to as PP1γ) differ mainly in the amino acid sequence of their C-terminal extension (Peti et al., 2013). PP1α and PP1γ display the highest sequence similarity and exhibit a distinct localization pattern during mitosis compared with PP1β (Fig. 1 C; Andreassen et al., 1998; Trinkle-Mulcahy et al., 2003). Biochemical and genetic data have shown that PP1 counteracts the activity of Cdk1, Aurora B, and Mps1 and regulates Plk1 activity (Francisco et al., 1994; Wang et al., 2008; Yamashiro et al., 2008; Wu et al., 2009; London et al., 2012; Nijenhuis et al., 2014).

PP2A in complex with specific B subunits control different aspects of mitosis

The PP2A active holoenzyme is a trimeric complex composed of a catalytic subunit (PP2ACα-β and PPP2CA-B), scaffolding A subunits (Aα-β, PR65A-B, and PPP2R1A-B), and one of four regulatory subunits: B (B55, PR55, and PPP2R2A-D), B′ (B56, PR61, and PPP2R5A-E), B′′ (PR48/PR70/PR130 and PPP2R3A-C), and B′′′ (Striatins or PR93/PR110) (Janssens and Goris, 2001; Shi, 2009). The 65-kD scaffolding A subunit is horseshoe shaped, and through its N-terminus, it interacts with the regulatory subunits while its C-terminus binds PP2AC (Fig. 2, B and C). The PP2AC-A complex is abundant in the cell while the regulatory subunits are rate-limiting for the formation of holoenzymes (Fig. 1 D; Bekker-Jensen et al., 2017). It is the PP2A-B55 and PP2A-B56 complexes that appear to be the major PP2A complexes regulating mitosis; however, they perform very distinct functions. PP2A-B55 counteracts Cdk1 activity to induce mitotic exit, whereas its activity is suppressed during the earlier stages of mitosis (Fig. 1 B; Castilho et al., 2009; Mochida et al., 2009; Schmitz et al., 2010; Cundell et al., 2016). PP2A-B56 associates with different mitotic structures and counteracts several mitotic kinases, such as Aurora B and Plk1 (Fig. 1 C; Foley et al., 2011; Suijkerbuijk et al., 2012; Hertz et al., 2016). B55 subunits are largely composed of a WD40 domain with an acidic surface facing toward the catalytic subunit. B56 subunits are composed of 15 tetratricopeptide repeats forming a horseshoe-shaped structure (Fig. 2, B and C; Xu et al., 2006, 2008; Cho and Xu, 2007). The four isoforms of B55 (B55α–δ) and five isoforms of B56 (B56α–ε) appear to be redundant, although expression levels of the different isoforms vary in different cell types and the B56 isoforms display distinct localization patterns (Foley et al., 2011; Bastos et al., 2014).

PP6, the least understood mitotic phosphatase

The PP6 holoenzyme is a trimeric complex composed of PP6C bound to one of three Sit4-associated proteins (SAPS) domain–containing subunits (PPP6R1-3 and SAPS 1–3) and one of three ankyrin repeat domain subunits (ANR28, ANR44, and ANR52; Luke et al., 1996; Stefansson et al., 2008; Guergnon et al., 2009; Zeng et al., 2010). The PPP6R subunits act as platforms for assembling the trimeric holoenzyme, and in yeast, the active complex is likely to be a dimer of PP6C and PPP6R because ANR subunits are not present in yeast (Guergnon et al., 2009). The N-terminal SAPS domain binds PP6C while a possibly unstructured C-terminal region binds an ANR subunit. The ANR subunits are predicted to be largely α helical in nature, similar to other ankyrin repeat proteins (Mosavi et al., 2004). PP6 controls Aurora A activity by dephosphorylating the T-loop during mitosis and counteracts casein kinase 2 (CK2; Zeng et al., 2010; Rusin et al., 2017).

While the mitotic phosphatases have very different compositions, they share a very similar catalytic subunit, the properties of which are discussed below.

PPP active site specificity or lack thereof

The structure of the PP1 catalytic subunit reveals that the catalytic domain of the PPP family is a compact, extremely conserved ∼35-kD structure with little variation in the residues in and surrounding the active site (Fig. 2 A; Egloff et al., 1995; Goldberg et al., 1995). The catalytic domain is a metalloenzyme with two metal ions bound in the active site that coordinate the phosphate group of the substrate and activate a water molecule for an in-line attack on the phosphate (Egloff et al., 1995; Goldberg et al., 1995; Zhang et al., 1996; Zhang and Lee, 1997; Swingle et al., 2004). PPPs are extremely efficient in catalysis; estimated to increase the rate of hydrolysis by a factor of 1021, they are one of the most efficient enzymes known (Swingle et al., 2004). The structures of PPP catalytic subunits reveal the absence of a clear peptide-binding cleft in the active site. There is, instead, an open surface with three putative spacious substrate-binding clefts that radiate from the catalytic center in a Y-shape: the C-terminal, hydrophobic, and acidic substrate-binding grooves (Fig. 2 A; Egloff et al., 1995; Goldberg et al., 1995). The structure of a mitotic PPP catalytic domain in complex with a substrate is not currently known. However, the structure of the catalytic domain of PP5, which is very similar to PP1 in structure, bound to a Cdc37 phosphomimetic peptide has been solved, as well as structures of PP2B and PP1 bound to phosphate (Griffith et al., 1995; Choy et al., 2014; Oberoi et al., 2016). The PP5-Cdc37 structure reveals that the substrate conformation is largely dictated by interactions between PP5 and the peptide backbone and that side chains of the substrate engage in water-mediated interactions with PP5, allowing the accommodation of a large array of side chains. In agreement with the PP5-Cdc37 structure, the sequence alignment of the known substrates of different PPPs reveals little sequence specificity beyond the actual phosphorylated residue (Li et al., 2013). This explains why PPPs can counteract multiple kinases but does not rule out that some sequence preference exists. As an example, in vitro assays with model peptides have shown that proline residues located C-terminally to the phosphorylation site is not a favorable circumstance for rapid dephosphorylation (Agostinis et al., 1987, 1990, 1992).

The use of isolated PPP enzymes in in vitro assays might poorly represent specificity because their association with specific binding partners controls specificity in vivo. An illustration of this is the structure of PP1 in complex with Mypt1 or Spinophilin (Terrak et al., 2004; Ragusa et al., 2010). In both instances, the PP1 active site does not undergo conformational changes; rather, Mypt1 reshapes the region around the active site by modulating its electrostatic properties while Spinophilin occupies the C-terminal cleft, thereby preventing the binding of substrates that rely on this groove. This suggests that many of the PP1 holoenzymes have unique substrate preferences despite the same active site. Whether this principle applies to other mitotic phosphatases is unknown and will require further structural and functional characterization.

Another feature of the PPP active site is a distinct preference for phosphothreonine over phosphoserine, an effect most clearly observed with PP2A but likely applicable to all PPP family members (Pinna et al., 1976; Agostinis et al., 1987; Deana and Pinna, 1988; Donella-Deana et al., 1990, 1994). The molecular basis for this phosphothreonine preference is not known, but a combined effect of a lower Km and higher Kcat on phosphothreonine substrates is recognized (Agostinis et al., 1987; Hein et al., 2017). It is possible that features of the active site contact the additional methyl group on threonine. Additionally, in vitro data also suggest that the nature of the metal ions in the active site influences this preference, but whether this is relevant in vivo is unclear (Agostinis et al., 1987). High-resolution structures of PPP-substrate complexes are needed to address this. As discussed later, this difference in the kinetics of phosphoserine and phosphothreonine is important for the orchestration of temporal events during mitosis and during the cell cycle in budding yeast (McCloy et al., 2015; Cundell et al., 2016; Godfrey et al., 2017; Hein et al., 2017). Many kinases also display preferences for phosphorylating either serine or threonine, and this will further influence the dynamics of a phosphorylation site (Chen et al., 2014).

It is evident from the structural and functional analysis of PPPs that the active site contributes a minimum of substrate specificity. So how is specificity achieved? As indicated, the substrate specificity of PPPs is achieved through the formation of a large number of holoenzymes the assembly of which I will discuss next.

Short linear-interaction motifs (SLiMs) control PP1 holoenzyme formation

How do PPPs assemble into multiple holoenzymes? An emerging theme is that distinct binding grooves on the catalytic subunit or binding pockets on the B regulatory subunits of PP2A recognize SLiMs in the unstructured regions of binding partners. These binding partners can be direct substrates, localize PPPs to specific mitotic structures for local dephosphorylation, or recruit specific substrates to the PPP. SLiMs are typically 4–10 amino acids long with two or three residues acting as core binding determinants and mediate low micromolar affinity interactions with globular domains (Tompa et al., 2014; Davey et al., 2015). A hallmark of SLiMs is that they are degenerate, thereby allowing a spectrum of affinities that can fine-tune signaling pathways; this is also the case for SLiMs binding to phosphatases. SLiMs control PPP specificity at multiple levels, for instance, by recruiting the phosphatase directly to a substrate, localizing it to a specific cellular compartment, or mediating the binding of an inhibitor or regulator to it.

One of the first SLiMs reported to bind a PPP family member was the RVxF motif that binds to a hydrophobic binding pocket on PP1 at a site distinct from the active site (Fig. 2 A; Egloff et al., 1997; Terrak et al., 2004). The RVxF motif is present in the vast majority of PP1-interacting proteins, and the motif is best described as (K/R)-(K/R)-(V/I)-(FIMYDP)-(F/W) (Wakula et al., 2003; Meiselbach et al., 2006; Moorhead et al., 2008; Hendrickx et al., 2009). These PP1-binding motifs are used to target PP1 to multiple proteins during mitosis, for example, the kinetochore protein Knl1 to regulate chromosome segregation and SAC silencing (Liu et al., 2010; Meadows et al., 2011; Nijenhuis et al., 2014), inhibitor 1 and 2 to regulate PP1 activity (Hurley et al., 2007; Marsh et al., 2010), Mypt1 to regulate Plk1 activity (Yamashiro et al., 2008; Matsumura et al., 2011; Dumitru et al., 2017), Kif18A to regulate chromosome oscillations (Häfner et al., 2014), and RepoMan and Ki67 to control chromosome decompaction and dephosphorylation of chromatin-associated factors (Trinkle-Mulcahy et al., 2006; Vagnarelli et al., 2011; Booth et al., 2014). A conserved interactor of PP1 is Sds22, which might act as a chaperone for PP1 holoenzymes because it binds to a distinct surface of PP1 without interfering with RVxF interactions (Ceulemans et al., 2002). However, the exact function of Sds22 and its effect on PP1 holoenzyme activity remain unclear, making it difficult to interpret the reported mitotic phenotypes of Sds22 removal (Ohkura and Yanagida, 1991; Peggie et al., 2002; Posch et al., 2010; Wurzenberger et al., 2012; Eiteneuer et al., 2014; Rodrigues et al., 2015).

How is the dynamic distribution of PP1 among all these binding partners controlled if the vast majority engages the RVxF-binding pocket on PP1? In several RVxF motifs, the x position is a phosphorylation site for Aurora kinases, which can consequently prevent the association of PP1 with the motif and thereby regulate PP1 holoenzyme formation (Nasa et al., 2018). For instance, the RVSF motif in the kinetochore protein Knl1 is phosphorylated by Aurora B, thereby dampening PP1 binding to kinetochores until microtubule attachment (Liu et al., 2010; Bajaj et al., 2018). Another distinct mechanism of phosphoregulation is the PP1 extended binding region of RepoMan (Fig. 2 A) that contains multiple Cdk1 phosphorylation sites, which prevent PP1 binding until anaphase (Qian et al., 2015). In addition to the RVxF motif, further motifs (e.g., SILK, ΦΦ, KiR-SLiM) have been described that bind to distinct grooves on PP1 (Hendrickx et al., 2009; Choy et al., 2014; Kumar et al., 2016). These motifs can be combined to tune the function and affinity of PP1 interactors as seen, for instance, with RepoMan and phosphatase 1 nuclear targeting subunits (PNUTS) that combine an RVxF motif, a ΦΦ motif, and an arginine residue to bind PP1 (Choy et al., 2014; Qian et al., 2015). In the crowded environment of the cell, these additional PP1 interaction motifs are important for controlling which holoenzymes are formed. Although the different isoforms of PP1 largely differ in their C-terminus and thus are all predicted to bind to the different PP1 binding motifs, recent elegant work has shown how subtle differences between PP1α and PP1γ can result in selective binding of PP1γ to RepoMan and Ki67 (Kumar et al., 2016).

The insight gained from analyzing PP1 holoenzymes has uncovered an unexpected level of complexity in their assembly and architecture. However, what is still lacking is a thorough understanding of what specific phosphorylation sites are targeted by specific PP1 holoenzymes in cells.

Substrate recognition by PP2A holoenzymes

In contrast to PP1, it has until recently been more enigmatic how PP2A holoenzymes recognize substrates. It is now clear that a conserved pocket on the B56 regulatory subunit binds to a SLiM, referred to as the LxxIxE motif present in multiple PP2A-B56 interactors (Hertz et al., 2016; Wang et al., 2016a,b; Wu et al., 2017). The LxxIxE motif was originally identified in the BubR1 checkpoint protein and subsequently in the protein RepoMan, providing the means to identify the motif in additional PP2A-B56 interactors (Suijkerbuijk et al., 2012; Kruse et al., 2013; Qian et al., 2013; Xu et al., 2013). In contrast to PP1-binding motifs in which phosphorylation blocks binding, for LxxIxE motifs phosphorylations within and downstream from the motif can rather increase PP2A-B56 binding, for instance, for controlling local interactions (Hertz et al., 2016). As an example, the interaction between the checkpoint protein BubR1 and PP2A-B56 is restricted to kinetochores because the BubR1 LxxIxE motif is only phosphorylated at kinetochores (Elowe et al., 2007, 2010; Huang et al., 2008; Kruse et al., 2013). Similarly, Aurora B and Plk1 likely control the association between RacGAP1 (Cyk4) and PP2A-B56 by phosphorylating the LxxIxE motif of RacGAP1 (Burkard et al., 2009; Hertz et al., 2016). While the LxxIxE motif binds to a conserved binding pocket present in all B56 isoforms, different isoforms display distinct localization patterns. For instance, B56γ and B56δ preferentially localize to kinetochores while B56γ and B56ε preferentially localize to the midzone during mitotic exit (Bastos et al., 2014; Nijenhuis et al., 2014). This localization is mediated by binding the LxxIxE motifs in BubR1 at kinetochores and Kif4A at the central spindle; however, it is presently unclear why only a subset of isoforms localizes to these structures. A possibility is that B56 isoform-specific contacts are present that further increase the affinity for BubR1 or Kif4A, leading to the preferential enrichment of isoforms.

Other important interactors of PP2A-B56 during mitosis are the Shugoshin proteins (SgoI and Sgo2) that protect centromeric cohesin through the recruitment of the phosphatase and might also affect kinetochore phosphorylations (Kitajima et al., 2006; Tang et al., 2006; Meppelink et al., 2015). However, SgoI does not contain an LxxIxE motif, binds a distinct region of B56, and contacts the catalytic subunit (Xu et al., 2009). The structure of the SgoI-PP2A-B56 complex has been determined by using a fragment of SgoI that has reduced binding affinity. Therefore, it is important that future work determines the structure of SgoI-PP2A-B56 containing the full binding domain of SgoI. It is puzzling that Sgo1 and Sgo2 also bind the protein SET, which is an inhibitor of PP2A and a histone chaperone (Li et al., 1996; Kitajima et al., 2006; Chambon et al., 2013). Why the Shugoshin proteins bind both PP2A-B56 and an inhibitor of this complex is unclear, but SET appears to also regulate the removal of Shugoshin proteins at later stages of mitosis (Krishnan et al., 2017).

The motif contributing to PP2A-B55 selectivity was discerned through a number of elegant mass spectrometry screens, which revealed that patches of basic residues upstream and downstream of SP or TP sites act as binding determinants of an acidic surface on the B55 regulatory subunit (Fig. 2 C; Cundell et al., 2016). Although direct binding between basic patches and PP2A-B55 still has to be demonstrated, the observations are consistent with the interaction between the Tau protein and SAMHD1 with PP2A-B55 (Xu et al., 2008; Schott et al., 2018). Several of the basic patches identified in PP2A-B55 substrates correspond to nuclear localization sequences in the targets. It is interesting to note that importin β has been proposed to regulate mitotic exit and bind to PP2A-B55 holoenzymes, raising the possibility that importin β can directly or indirectly regulate dephosphorylation of PP2A-B55 substrates (Schmitz et al., 2010). Importantly, the number of basic residues controls PP2A-B55 dephosphorylation kinetics, thus providing a mechanism for achieving temporal dephosphorylation of Cdk1 sites during mitotic exit and, thereby, coordination of mitotic exit events. This is in line with how temporal dephosphorylation by Cdc14, the budding yeast mitotic exit phosphatase, is guided by differences in catalytic efficiency among its substrates that is, in part, controlled by differences in binding affinities to substrates (Bouchoux and Uhlmann, 2011). It is thus possible that a general principle controlling temporal dephosphorylation of mitotic exit substrates is the affinity of the phosphatases for substrates. Furthermore, meticulous reconstitution experiments with Cdc14 substrates have revealed that substrates with high catalytic efficiency delay the dephosphorylation of substrates with lower catalytic efficiency due to competition (Bouchoux and Uhlmann, 2011). Therefore, it is important that future work encompasses similar in vitro reconstitution experiments with PP2A complexes to investigate how dephosphorylation kinetics is affected by competition. Although substrate affinity is an important parameter, the amino acid composition of and surrounding the phosphorylation site is also important for controlling dephosphorylation kinetics. PP2A-B55 has a strong preference for phosphothreonine, and this orchestrates mitotic exit events (Cundell et al., 2016; Hein et al., 2017). Furthermore, the dephosphorylation kinetics of SP and TP sites is affected by the +2 position. A small, nonpolar amino acid in position +2 (S/TP-Gly sites) favors dephosphorylation while a proline in +2 (S/TP-Pro sites) hinders dephosphorylation, possibly due to restricted flexibility (McCloy et al., 2015).

Although our understanding of how PP2A-B56 and PP2A-B55 recognize their substrates has dramatically increased, it is very likely that further motifs in addition to the LxxIxE motif and basic patches contribute to recognition, as observed for PP1. For instance, additional contacts to the B subunits, scaffold subunit or catalytic subunit are all possible. In line with this idea, the sequence in the Eya1-4 proteins mediating binding to PP2A-B55 is very distinct from a basic patch (Zhang et al., 2018). Therefore, defining these putative motifs and understanding their role in mitotic regulation are important future goals.

PP6 regulation of mitosis

PP6 has been shown to regulate mitotic progression in yeast, flies, and human cells (Shimanuki et al., 1993; Bastians and Ponstingl, 1996; Goshima et al., 2003; Chen et al., 2007; Zeng et al., 2010). For instance, PP6 complexes control Aurora A activity through T-loop dephosphorylation as well as regulating components of the condensin I complex by removing CK2 phosphorylations (Zeng et al., 2010; Hammond et al., 2013; Rusin et al., 2015). Indeed, phosphoproteomic studies suggest that PP6 complexes act to counteract multiple CK2 sites during mitosis (Rusin et al., 2017). Currently, our understanding of how PP6 complexes recognize substrates is limited and, in principle, both the PPP6R subunits and ANR subunits could contribute to substrate selection. Because the PPP6R and ANR subunits contain folded domains, it is possible that they recognize SLiMs in substrates and regulators; however, this notion awaits validation. Alternatively, the unstructured region of PPP6R subunits could potentially bind to globular domains of substrates, as seen with Cdc25A, which uses the RxL motif to bind cyclins (Saha et al., 1997). The findings of a recent study possibly point in this direction in that the targeting of Plk1 to the PP6-ANR28-PPP6R2 complex occurs through phosphorylation of the unstructured region of PPP6R2, thereby creating a binding site for the polo-box domain of Plk1 (Kettenbach et al., 2018). The recruitment of Plk1 to PP6-ANKR28-PP6R2 seems to negatively regulate the complex, thus ensuring high levels of Aurora A activity during mitosis through suppression of Aurora A T-loop dephosphorylation.

Because PP6 is the least understood mitotic phosphatase, a fuller understanding of both the structural organization of the complex and its substrate recognition principles is an important goal for the future.

Regulation of mitotic phosphatase activities

Having described some of the basic principles of substrate recognition by protein phosphatases, I will now focus on the regulation of their activity because this is critical for proper cell division.

The regulation of inhibitory phosphorylations on Cdk1 controlled by Wee1/Myt1 kinases and Cdc25 phosphatases has been a fundamental model for describing entry into mitosis (Boutros et al., 2006; Lindqvist et al., 2009). It is now evident that, in addition to activating Cdk1, it is important to inhibit PP2A-B55, which appears to be a major Cdk1-antagonizing phosphatase (Agostinis et al., 1992; Mayer-Jaekel et al., 1993; Castilho et al., 2009; Mochida et al., 2009, 2010; Vigneron et al., 2009; Gharbi-Ayachi et al., 2010; Schmitz et al., 2010; Cundell et al., 2016). The pathway leading to PP2A-B55 inhibition has been extensively characterized and initiates with Cdk1 activation of the Mastl (Greatwall) kinase through phosphorylation of Cdk1 sites in Mastl (Fig. 3; Vigneron et al., 2011; Blake-Hodek et al., 2012). Upon Cdk1 phosphorylation, Mastl autophosphorylates, resulting in activation of the kinase. The relevant targets of Mastl are two small proteins, ENSA and Arpp19, that when phosphorylated by Mastl are transformed into potent inhibitors of PP2A-B55 (Gharbi-Ayachi et al., 2010; Mochida et al., 2010). ENSA and Arpp19 share a short common Mastl phosphorylation motif, FDSGDY, that when phosphorylated inhibits PP2A-B55 with the phosphorylated residue binding to the active site of PP2A-B55 (Mochida, 2014). Interestingly, ENSA and Arpp19 inhibit PP2A-B55 by acting as substrates that are slowly dephosphorylated, and thus, when Mastl activity is turned off, PP2A-B55 activates itself by dephosphorylating ENSA and Arpp19 (Williams et al., 2014). Given that ENSA and Arpp19 are present at only roughly fivefold higher levels than PP2A-B55, activation of this phosphatase occurs in approximately 1 min after Mastl inactivation, ensuring rapid mitotic exit (Williams et al., 2014). This model has been termed “inhibition by unfair competition,” and a similar mechanism has been shown to control the activity of the PP1-Mypt1 complex by the small protein inhibitor CPI-17 and could potentially be a general mechanism for controlling phosphatase activity (Filter et al., 2017). A small protein termed Bod1 has been proposed to be an inhibitor of PP2A-B56, and Bod1 is also phosphorylated to inhibit PP2A-B56; however, whether Bod1 inhibits through unfair competition is presently unclear (Porter et al., 2013). It should also be noted that Cdk1 might directly inhibit PP2A complexes through phosphorylation of a TP site in the C-terminal region of the catalytic domain, although the role of this in mitotic regulation has yet to be investigated (Evans and Hemmings, 2000; Longin et al., 2007; Kettenbach et al., 2011).

Mitotic phosphatases in disease

The mitotic phosphatases generally act as tumor suppressors through dephosphorylation of substrates of oncogenic kinases. In most instances, it is unclear if the role of the phosphatases in mitosis plays a role in disease progression. PP2A was identified as the target of the small tumor antigen of the transforming viruses SV40 and polyomavirus, and small tumor antigen appears to mainly displace B56γ from the PP2A holoenzyme (Chen et al., 2004; Mumby, 2007). In addition, loss-of-function mutations in the PP2A scaffolding subunits as well as B56 regulatory subunits have been identified in a number of cancers and linked to intellectual disability and developmental disorders (Chen et al., 2005; Sablina et al., 2007; Nobumori et al., 2012; Houge et al., 2015; Haesen et al., 2016). The B55α subunit is down-regulated in prostate cancer, and PP2A-B55 might also affect the progression of Alzheimer’s disease through dephosphorylation of the Tau protein (Gong et al., 1995; Cheng et al., 2011; Mao et al., 2011). An additional mechanism of PP2A inhibition in cancers is through the overexpression of CIP2A and SET, which are inhibitors of the phosphatase (Junttila et al., 2007; Zhou et al., 2017). PP2A-B56 also acts as a host factor for the Ebola virus while the HIV virus down-regulates PP2A-B56 (Greenwood et al., 2016; Kruse et al., 2018). Given the central role of PP2A in several human diseases, the development of PP2A modulators that either increase or decrease its activity is being developed (Lai et al., 2018; McClinch et al., 2018). PP6C is mutated in melanomas, and these mutations prevent the assembly of PP6 holoenzymes and hereby inhibit the phosphatase (Hodis et al., 2012; Krauthammer et al., 2012; Hammond et al., 2013). The PP6C mutations identified in cancers have been shown to cause chromosome missegregation because of increased Aurora A activity, and there is, thus, a link between PP6C mutations and their role in mitosis (Hammond et al., 2013). In addition, the PP6 holoenzymes have been identified as host factors for the influenza A virus (York et al., 2014). Disease mutations in PP1β have been linked to intellectual disabilities and delayed development, but if this is through an effect on mitosis is not clear (Hamdan et al., 2014; Ma et al., 2016a).

Activating phosphatases to promote mitotic exit

Anaphase marks the point of no return because the cells commit to mitotic exit, and in this and the following section, I will focus on the role and regulation of mitotic phosphatases in controlling mitotic exit events. This will illustrate the complex cross-talk between phosphatases and kinases and how regulated phosphatase binding helps coordinate mitotic events. Based on the “inhibition by unfair competition” model, the key event for activating PP2A-B55 is inactivation of Mastl through dephosphorylation. Removal of Cdk1 sites on Mastl is initiated by PP1, and then once PP2A-B55 is activated, it can also dephosphorylate Mastl (Heim et al., 2015; Ma et al., 2016b; Rogers et al., 2016; Ren et al., 2017). There is some disagreement on which Mastl phosphorylation sites are dephosphorylated by PP1, and it is also unclear if a specific PP1 holoenzyme is responsible because multiple PP1 regulatory subunits have been identified in Mastl purifications (Rogers et al., 2016; Ren et al., 2017). The Fcp1 phosphatase has also been implicated in dephosphorylation of ENSA and Mastl, but given the essential role of Fcp1 in dephosphorylating the RNA polymerase C-terminal domain, these data are difficult to interpret (Visconti et al., 2012; Hégarat et al., 2014; Williams et al., 2014). Furthermore, studies of fission yeast suggest that PP1 directly binds PP2A-B55 through an RVxF motif in B55 to activate PP2A-B55, and this mechanism might also extend to humans because the binding site for PP1 in B55 is conserved (Grallert et al., 2015). In fission yeast, the activated PP2A-B55 dephosphorylates B56 subunits to allow binding of PP1 and activation of PP2A-B56 (Grallert et al., 2015).

What initiates PP1-mediated dephosphorylation of Mastl? One mechanistic proposal is that PP1 activity is directly inhibited through the cyclin B1-Cdk1 phosphorylation of a C-terminal phosphorylation site (Thr320 in PP1γ). Indeed, phosphomimetic substitution of Thr320 inactivates PP1 and inhibits mitotic exit (Dohadwala et al., 1994; Kwon et al., 1997; Wu et al., 2009; Grallert et al., 2015). At metaphase, when the APC/C-Cdc20 complex is activated and initiates cyclin B1 degradation and thereby Cdk1 inactivation, PP1 autodephosphorylates, leading to its activation (Wu et al., 2009). Modeling suggests that Cdk1 activity has to be reduced by 90% before PP1 gets activated; however, this seems inconsistent with how fast PP2A-B55 is activated and the reported rates of cyclin B1 degradation (Clute and Pines, 1999; Cundell et al., 2013; Rogers et al., 2016). This inconsistency is possibly explained by the fact that the stoichiometry of Thr320 phosphorylation is 60% in prometaphase-arrested cells, which would not be sufficient to fully inhibit PP1 (Olsen et al., 2010). Consistent with PP1 being active in prometaphase is the observation that the mutation of the RVxF motif in Knl1 leads to an increased phosphorylation of Knl1 MELT repeats that are targeted by PP1 (Nijenhuis et al., 2014; Zhang et al., 2014). Second, the addition of PP1 T320A, which cannot be inhibited by Cdk1, to a Xenopus laevis extract only promotes mitotic exit at protein levels 8 times higher than endogenous PP1 while lower levels of PP1 T320A have no effect (Wu et al., 2009). A search for additional PP1 inhibitory activities that control PP1 during mitosis identified inhibitor 1 (PPP1R1A, expressed only in vertebrates) as this activity. Inhibitor 1, when phosphorylated by PKA, inhibits PP1, and similar to ENSA/Arpp19, PP1 dephosphorylates inhibitor 1 to release PP1 from inhibition (Wu et al., 2009). The combined action of PP1 Thr320 phosphorylation and inhibitor 1 is likely to be important for constraining PP1 activity. However, the picture is even more complicated because inhibitor 2 regulates PP1 mitotic activity and is possibly regulated by Cdk1 phosphorylation (Villa-Moruzzi, 1992; Puntoni and Villa-Moruzzi, 1995; Tung et al., 1995; Wang et al., 2008).

Although the complexity of the mechanisms regulating mitotic exit is beginning to unfold, there are currently many unknown parameters that need to be determined to fully understand how mitotic exit is regulated. How does PP1 activity change both temporally and spatially during mitosis? What are the PP1 complexes that coordinate Mastl dephosphorylation to promote exit? Is Mastl activity locally controlled—as indicated by immunofluorescence analysis with a phosphospecific antibody recognizing a Cdk1-activating phosphorylation in Mastl (Hégarat et al., 2014)—and, if so, how? Furthermore, a temporal and quantitative description of all important phosphorylation sites and their stoichiometry, as well as the kinases and phosphatases involved, is needed to gain a proper understanding and modeling of mitotic exit. This could possibly be achieved by mass spectrometry, although this method lacks spatial information that has often transpired to be critical in the regulation of mitosis.

Regulation of APC/C-Cdc20 activity by phosphatases

The activity of APC/C-Cdc20 is tightly controlled because this complex is responsible for degrading cyclin B1 and thereby promoting mitotic exit at two levels: turning off Cdk1 and activating PP2A-B55 indirectly through turning off Mastl. Phosphatases regulate APC/C activity at two levels: directly through dephosphorylation of Cdc20 and APC/C subunits and indirectly through phosphatase-mediated silencing of checkpoint signaling from the kinetochores.

Improperly attached kinetochores activate the SAC to inhibit APC/C-Cdc20 activity, which ensures proper biorientation of chromosomes before anaphase is initiated (Lara-Gonzalez et al., 2012). The recruitment of Mps1 kinase to kinetochores initiates a phosphorylation cascade, including the MELT repeats in the Knl1 kinetochore protein, phosphorylation sites in the Bub1 checkpoint protein to facilitate Mad1 binding, and phosphorylation of Mad1 leading to its activation (Fig. 4; London et al., 2012; Shepperd et al., 2012; Yamagishi et al., 2012; Faesen et al., 2017; Ji et al., 2017; Zhang et al., 2017). It has been suggested that Mps1 is activated by Cdk1 phosphorylation and inactivated by PP2A-B55 dephosphorylation, although different Mps1 phosphorylation sites were studied (Morin et al., 2012; Diril et al., 2016). This explains the dependency of the checkpoint on Cdk1 activity, although Mps1 is likely not the only target of Cdk1 in the checkpoint (Vázquez-Novelle et al., 2014). The MELT repeats in Knl1 act as binding sites for Bub1-Bub3 and BubR1-Bub3, and this indirectly results in the recruitment of PP2A-B56 through direct binding of the phosphatase to BubR1 (Suijkerbuijk et al., 2012; Kruse et al., 2013; Xu et al., 2013). This kinetochore-localized pool of PP2A-B56 counteracts Aurora B activity to facilitate kinetochore-microtubule interactions through dephosphorylation of kinetochore proteins and negatively regulates checkpoint signaling by dephosphorylating Bub1 to prevent its binding to Mad1 and the RVxF motif in Knl1 to promote PP1 binding (Foley et al., 2011; Suijkerbuijk et al., 2012; Nijenhuis et al., 2014; Qian et al., 2017). PP2A-B56–mediated dephosphorylation of Bub1 has been proposed to act as a timer in the checkpoint, thereby restricting the Bub1-Mad1 interaction to a limited window in the early stages of mitosis. This timer is established by a delay in the recruitment of PP2A-B56 to kinetochores compared with Bub1 and Mps1 (Qian et al., 2017). The dephosphorylation of the RVxF motif in Knl1 results in the recruitment of PP1 and the dephosphorylation of MELT motifs, thereby preventing the binding of Bub proteins and turning off the checkpoint (Meadows et al., 2011; Rosenberg et al., 2011; London et al., 2012; Nijenhuis et al., 2014; Zhang et al., 2014). It is possible that PP2A-B56 bound to BubR1 can also dephosphorylate MELT repeats, and it might be that PP1 and PP2A-B56 act somewhat redundantly in dephosphorylating Knl1 (Espert et al., 2014). Such a redundancy could explain the minor delays in the checkpoint silencing observed in cells expressing Knl1 with a mutated RVxF motif or BubR1 with a mutated LxxIxE motif (Espeut et al., 2012; Espert et al., 2014; Nijenhuis et al., 2014; Zhang et al., 2014). Alternatively, PP1 and PP2A-B56 might act on multiple substrates to turn off checkpoint signaling, and simply preventing the dephosphorylation of a subset of substrates is insufficient to strongly impair checkpoint silencing. Furthermore, additional kinetochore interactors for PP1 exist, such as Mypt1, ELYS, Kif18A, CENP-E, and the Ska complex; however, the exact contribution of these PP1 interactors to SAC silencing is unclear (Yamashiro et al., 2008; Kim et al., 2010; Matsumura et al., 2011; Meadows et al., 2011; Häfner et al., 2014; Hattersley et al., 2016; Sivakumar et al., 2016). Understanding how closely localized kinetochore phosphatases precisely select the residues to be dephosphorylated in a temporal, controlled manner is clearly an important but challenging topic.

When the SAC signal is turned off at kinetochores, APC/C-Cdc20 becomes active, and this requires selective dephosphorylation of Cdc20 (Labit et al., 2012; Craney et al., 2016; Hein et al., 2017; Kim et al., 2017; Lee et al., 2017). Cdc20 is inhibited by phosphorylation on multiple sites by Cdk1 and Bub1, and these have to be removed while still maintaining activating Cdk1 phosphorylations on APC/C (Fujimitsu et al., 2016; Qiao et al., 2016; Zhang et al., 2016). This selective dephosphorylation of Cdc20 can at least, in part, be attributed to the fact that Cdk1 inhibitory sites in Cdc20 are TP while activating Cdk1 sites in APC/C are SP, resulting in selective Cdc20 dephosphorylation by PP2A-B55 due to its inherent preference for phosphothreonine (Hein et al., 2017). However, PP2A-B55 cannot be the only phosphatase for Cdc20 because APC/C-Cdc20 must be activated before PP2A-B55 to initiate Mastl inactivation. The identity of this phosphatase awaits discovery, but work in Xenopus suggests that it might be a PP2A complex and, indeed, PP2A-B56 has been shown to interact with APC/C in early mitosis (Labit et al., 2012; Craney et al., 2016; Lee et al., 2017). Furthermore, PP1 has been implicated in controlling Cdc20 dephosphorylation in worms (Kim et al., 2017). Understanding mitotic exit will require a full understanding of how different phosphatases regulate APC/C-Cdc20.

Major obstacles and possible solutions

While the central role of PPPs in regulating mitosis has been recognized for decades, it is only recently that the complexity of their regulation and targeting has started to unfold. However, a major impediment still remaining is our limited understanding of the precise substrates of the different PPP holoenzymes due to the absence of tools to precisely inhibit these complexes. This prevents the system-wide substrate identification that has been achieved for mitotic kinases. One solution is to generate more selective inhibitors for PPPs and specific holoenzymes, and progress has indeed been made in this direction (Fontanillo et al., 2016; Choy et al., 2017; Krzyzosiak et al., 2018). Alternatively, as our understanding of substrate recognition increases, it might be possible to target the phosphatase-SLiM interactions because they are low micromolar affinity interactions. Indeed, the immunosuppressants FK506 and cyclosporin A target the SLiM-binding pocket of Calcineurin, confirming that this is a potential strategy (Grigoriu et al., 2013). Establishment of the “phosphatome” for the different mitotic phosphatases and potentially specific holoenzymes would clearly allow for a better understanding of how these enzymes coordinate different mitotic events. However, such approaches would need to be complemented with meticulous in vitro assays to determine dephosphorylation kinetics and how this is influenced by the affinity, position, and nature of phosphorylation sites. From such systematic analyses, it might be possible to extract general principles that could be useful in interpreting the “phosphatome” data. Such combined information would not only provide an important overview but also help in the design of more precise experiments aimed at addressing the function of specific mitotic phosphatases.

Acknowledgments

I thank Wolfgang Peti, Rebecca Page, Arminja Kettenbach, Fabian Coscia, and Thomas Kruse for commenting on the manuscript and fruitful discussions. Furthermore, Wolfgang Peti and Rebecca Page kindly provided the model of RepoMan peptide in complex with the PP2A-B56 holoenzyme.

This work was supported by a grant from the Novo Nordisk Foundation (NNF14CC0001).

The author declares no competing financial interests.

References

References
Afshar
,
K.
,
M.E.
Werner
,
Y.C.
Tse
,
M.
Glotzer
, and
P.
Gönczy
.
2010
.
Regulation of cortical contractility and spindle positioning by the protein phosphatase 6 PPH-6 in one-cell stage C. elegans embryos
.
Development.
137
:
237
247
.
Agostinis
,
P.
,
J.
Goris
,
E.
Waelkens
,
L.A.
Pinna
,
F.
Marchiori
, and
W.
Merlevede
.
1987
.
Dephosphorylation of phosphoproteins and synthetic phosphopeptides. Study of the specificity of the polycation-stimulated and MgATP-dependent phosphorylase phosphatases
.
J. Biol. Chem.
262
:
1060
1064
.
Agostinis
,
P.
,
J.
Goris
,
L.A.
Pinna
,
F.
Marchiori
,
J.W.
Perich
,
H.E.
Meyer
, and
W.
Merlevede
.
1990
.
Synthetic peptides as model substrates for the study of the specificity of the polycation-stimulated protein phosphatases
.
Eur. J. Biochem.
189
:
235
241
.
Agostinis
,
P.
,
R.
Derua
,
S.
Sarno
,
J.
Goris
, and
W.
Merlevede
.
1992
.
Specificity of the polycation-stimulated (type-2A) and ATP,Mg-dependent (type-1) protein phosphatases toward substrates phosphorylated by P34cdc2 kinase
.
Eur. J. Biochem.
205
:
241
248
.
Andreassen
,
P.R.
,
F.B.
Lacroix
,
E.
Villa-Moruzzi
, and
R.L.
Margolis
.
1998
.
Differential subcellular localization of protein phosphatase-1 alpha, gamma1, and delta isoforms during both interphase and mitosis in mammalian cells
.
J. Cell Biol.
141
:
1207
1215
.
Bajaj
,
R.
,
M.
Bollen
,
W.
Peti
, and
R.
Page
.
2018
.
KNL1 Binding to PP1 and Microtubules Is Mutually Exclusive
.
Structure.
26
:
1327
1336.e4
.
Bastians
,
H.
, and
H.
Ponstingl
.
1996
.
The novel human protein serine/threonine phosphatase 6 is a functional homologue of budding yeast Sit4p and fission yeast ppe1, which are involved in cell cycle regulation
.
J. Cell Sci.
109
:
2865
2874
.
Bastos
,
R.N.
,
M.J.
Cundell
, and
F.A.
Barr
.
2014
.
KIF4A and PP2A-B56 form a spatially restricted feedback loop opposing Aurora B at the anaphase central spindle
.
J. Cell Biol.
207
:
683
693
.
Bekker-Jensen
,
D.B.
,
C.D.
Kelstrup
,
T.S.
Batth
,
S.C.
Larsen
,
C.
Haldrup
,
J.B.
Bramsen
,
K.D.
Sørensen
,
S.
Høyer
,
T.F.
Ørntoft
,
C.L.
Andersen
, et al
2017
.
An Optimized Shotgun Strategy for the Rapid Generation of Comprehensive Human Proteomes
.
Cell Syst.
4
:
587
599.e4
.
Blake-Hodek
,
K.A.
,
B.C.
Williams
,
Y.
Zhao
,
P.V.
Castilho
,
W.
Chen
,
Y.
Mao
,
T.M.
Yamamoto
, and
M.L.
Goldberg
.
2012
.
Determinants for activation of the atypical AGC kinase Greatwall during M phase entry
.
Mol. Cell. Biol.
32
:
1337
1353
.
Booher
,
R.
, and
D.
Beach
.
1989
.
Involvement of a type 1 protein phosphatase encoded by bws1+ in fission yeast mitotic control
.
Cell.
57
:
1009
1016
.
Booth
,
D.G.
,
M.
Takagi
,
L.
Sanchez-Pulido
,
E.
Petfalski
,
G.
Vargiu
,
K.
Samejima
,
N.
Imamoto
,
C.P.
Ponting
,
D.
Tollervey
,
W.C.
Earnshaw
, and
P.
Vagnarelli
.
2014
.
Ki-67 is a PP1-interacting protein that organises the mitotic chromosome periphery
.
eLife.
3
:
e01641
.
Bouchoux
,
C.
, and
F.
Uhlmann
.
2011
.
A quantitative model for ordered Cdk substrate dephosphorylation during mitotic exit
.
Cell.
147
:
803
814
.
Boutros
,
R.
,
C.
Dozier
, and
B.
Ducommun
.
2006
.
The when and wheres of CDC25 phosphatases
.
Curr. Opin. Cell Biol.
18
:
185
191
.
Burkard
,
M.E.
,
J.
Maciejowski
,
V.
Rodriguez-Bravo
,
M.
Repka
,
D.M.
Lowery
,
K.R.
Clauser
,
C.
Zhang
,
K.M.
Shokat
,
S.A.
Carr
,
M.B.
Yaffe
, and
P.V.
Jallepalli
.
2009
.
Plk1 self-organization and priming phosphorylation of HsCYK-4 at the spindle midzone regulate the onset of division in human cells
.
PLoS Biol.
7
:
e1000111
.
Castilho
,
P.V.
,
B.C.
Williams
,
S.
Mochida
,
Y.
Zhao
, and
M.L.
Goldberg
.
2009
.
The M phase kinase Greatwall (Gwl) promotes inactivation of PP2A/B55delta, a phosphatase directed against CDK phosphosites
.
Mol. Biol. Cell.
20
:
4777
4789
.
Ceulemans
,
H.
,
V.
Vulsteke
,
M.
De Maeyer
,
K.
Tatchell
,
W.
Stalmans
, and
M.
Bollen
.
2002
.
Binding of the concave surface of the Sds22 superhelix to the alpha 4/alpha 5/alpha 6-triangle of protein phosphatase-1
.
J. Biol. Chem.
277
:
47331
47337
.
Chambon
,
J.-P.
,
S.A.
Touati
,
S.
Berneau
,
D.
Cladière
,
C.
Hebras
,
R.
Groeme
,
A.
McDougall
, and
K.
Wassmann
.
2013
.
The PP2A inhibitor I2PP2A is essential for sister chromatid segregation in oocyte meiosis II
.
Curr. Biol.
23
:
485
490
.
Chen
,
C.
,
B.H.
Ha
,
A.F.
Thévenin
,
H.J.
Lou
,
R.
Zhang
,
K.Y.
Yip
,
J.R.
Peterson
,
M.
Gerstein
,
P.M.
Kim
,
P.
Filippakopoulos
, et al
2014
.
Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity
.
Mol. Cell.
53
:
140
147
.
Chen
,
F.
,
V.
Archambault
,
A.
Kar
,
P.
Lio’
,
P.P.
D’Avino
,
R.
Sinka
,
K.
Lilley
,
E.D.
Laue
,
P.
Deák
,
L.
Capalbo
, and
D.M.
Glover
.
2007
.
Multiple protein phosphatases are required for mitosis in Drosophila
.
Curr. Biol.
17
:
293
303
.
Chen
,
M.J.
,
J.E.
Dixon
, and
G.
Manning
.
2017
.
Genomics and evolution of protein phosphatases
.
Sci. Signal.
10
:
eaag1796
.
Chen
,
W.
,
R.
Possemato
,
K.T.
Campbell
,
C.A.
Plattner
,
D.C.
Pallas
, and
W.C.
Hahn
.
2004
.
Identification of specific PP2A complexes involved in human cell transformation
.
Cancer Cell.
5
:
127
136
.
Chen
,
W.
,
J.D.
Arroyo
,
J.C.
Timmons
,
R.
Possemato
, and
W.C.
Hahn
.
2005
.
Cancer-associated PP2A Aalpha subunits induce functional haploinsufficiency and tumorigenicity
.
Cancer Res.
65
:
8183
8192
.
Cheng
,
Y.
,
W.
Liu
,
S.-T.
Kim
,
J.
Sun
,
L.
Lu
,
J.
Sun
,
S.L.
Zheng
,
W.B.
Isaacs
, and
J.
Xu
.
2011
.
Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study
.
Cancer Genet.
204
:
375
381
.
Cho
,
U.S.
, and
W.
Xu
.
2007
.
Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme
.
Nature.
445
:
53
57
.
Choy
,
M.S.
,
M.
Hieke
,
G.S.
Kumar
,
G.R.
Lewis
,
K.R.
Gonzalez-DeWhitt
,
R.P.
Kessler
,
B.J.
Stein
,
M.
Hessenberger
,
A.C.
Nairn
,
W.
Peti
, and
R.
Page
.
2014
.
Understanding the antagonism of retinoblastoma protein dephosphorylation by PNUTS provides insights into the PP1 regulatory code
.
Proc. Natl. Acad. Sci. USA.
111
:
4097
4102
.
Choy
,
M.S.
,
M.
Swingle
,
B.
D’Arcy
,
K.
Abney
,
S.F.
Rusin
,
A.N.
Kettenbach
,
R.
Page
,
R.E.
Honkanen
, and
W.
Peti
.
2017
.
PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors
.
J. Am. Chem. Soc.
139
:
17703
17706
.
Clifford
,
D.M.
,
C.-T.
Chen
,
R.H.
Roberts
,
A.
Feoktistova
,
B.A.
Wolfe
,
J.-S.
Chen
,
D.
McCollum
, and
K.L.
Gould
.
2008
.
The role of Cdc14 phosphatases in the control of cell division
.
Biochem. Soc. Trans.
36
:
436
438
.
Clute
,
P.
, and
J.
Pines
.
1999
.
Temporal and spatial control of cyclin B1 destruction in metaphase
.
Nat. Cell Biol.
1
:
82
87
.
Craney
,
A.
,
A.
Kelly
,
L.
Jia
,
I.
Fedrigo
,
H.
Yu
, and
M.
Rape
.
2016
.
Control of APC/C-dependent ubiquitin chain elongation by reversible phosphorylation
.
Proc. Natl. Acad. Sci. USA.
113
:
1540
1545
.
Cundell
,
M.J.
,
R.N.
Bastos
,
T.
Zhang
,
J.
Holder
,
U.
Gruneberg
,
B.
Novak
, and
F.A.
Barr
.
2013
.
The BEG (PP2A-B55/ENSA/Greatwall) pathway ensures cytokinesis follows chromosome separation
.
Mol. Cell.
52
:
393
405
.
Cundell
,
M.J.
,
L.H.
Hutter
,
R.
Nunes Bastos
,
E.
Poser
,
J.
Holder
,
S.
Mohammed
,
B.
Novak
, and
F.A.
Barr
.
2016
.
A PP2A-B55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit
.
J. Cell Biol.
214
:
539
554
.
Davey
,
N.E.
,
M.S.
Cyert
, and
A.M.
Moses
.
2015
.
Short linear motifs - ex nihilo evolution of protein regulation
.
Cell Commun. Signal.
13
:
43
.
Deana
,
A.D.
, and
L.A.
Pinna
.
1988
.
Identification of pseudo ‘phosphothreonyl-specific’ protein phosphatase T with a fraction of polycation-stimulated protein phosphatase 2A
.
Biochim. Biophys. Acta.
968
:
179
185
.
Diril
,
M.K.
,
X.
Bisteau
,
M.
Kitagawa
,
M.J.
Caldez
,
S.
Wee
,
J.
Gunaratne
,
S.H.
Lee
, and
P.
Kaldis
.
2016
.
Loss of the Greatwall Kinase Weakens the Spindle Assembly Checkpoint
.
PLoS Genet.
12
:
e1006310
.
Dohadwala
,
M.
,
E.F.
da Cruz e Silva
,
F.L.
Hall
,
R.T.
Williams
,
D.A.
Carbonaro-Hall
,
A.C.
Nairn
,
P.
Greengard
, and
N.
Berndt
.
1994
.
Phosphorylation and inactivation of protein phosphatase 1 by cyclin-dependent kinases
.
Proc. Natl. Acad. Sci. USA.
91
:
6408
6412
.
Donella-Deana
,
A.
,
C.H.
Mac Gowan
,
P.
Cohen
,
F.
Marchiori
,
H.E.
Meyer
, and
L.A.
Pinna
.
1990
.
An investigation of the substrate specificity of protein phosphatase 2C using synthetic peptide substrates; comparison with protein phosphatase 2A
.
Biochim. Biophys. Acta.
1051
:
199
202
.
Donella-Deana
,
A.
,
M.H.
Krinks
,
M.
Ruzzene
,
C.
Klee
, and
L.A.
Pinna
.
1994
.
Dephosphorylation of phosphopeptides by calcineurin (protein phosphatase 2B)
.
Eur. J. Biochem.
219
:
109
117
.
Doonan
,
J.H.
, and
N.R.
Morris
.
1989
.
The bimG gene of Aspergillus nidulans, required for completion of anaphase, encodes a homolog of mammalian phosphoprotein phosphatase 1
.
Cell.
57
:
987
996
.
Dumitru
,
A.M.G.
,
S.F.
Rusin
,
A.E.M.
Clark
,
A.N.
Kettenbach
, and
D.A.
Compton
.
2017
.
Cyclin A/Cdk1 modulates Plk1 activity in prometaphase to regulate kinetochore-microtubule attachment stability
.
eLife.
6
:
e29303
.
Egloff
,
M.P.
,
P.T.
Cohen
,
P.
Reinemer
, and
D.
Barford
.
1995
.
Crystal structure of the catalytic subunit of human protein phosphatase 1 and its complex with tungstate
.
J. Mol. Biol.
254
:
942
959
.
Egloff
,
M.P.
,
D.F.
Johnson
,
G.
Moorhead
,
P.T.
Cohen
,
P.
Cohen
, and
D.
Barford
.
1997
.
Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1
.
EMBO J.
16
:
1876
1887
.
Eiteneuer
,
A.
,
J.
Seiler
,
M.
Weith
,
M.
Beullens
,
B.
Lesage
,
V.
Krenn
,
A.
Musacchio
,
M.
Bollen
, and
H.
Meyer
.
2014
.
Inhibitor-3 ensures bipolar mitotic spindle attachment by limiting association of SDS22 with kinetochore-bound protein phosphatase-1
.
EMBO J.
33
:
2704
2720
.
Elowe
,
S.
,
S.
Hümmer
,
A.
Uldschmid
,
X.
Li
, and
E.A.
Nigg
.
2007
.
Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions
.
Genes Dev.
21
:
2205
2219
.
Elowe
,
S.
,
K.
Dulla
,
A.
Uldschmid
,
X.
Li
,
Z.
Dou
, and
E.A.
Nigg
.
2010
.
Uncoupling of the spindle-checkpoint and chromosome-congression functions of BubR1
.
J. Cell Sci.
123
:
84
94
.
Espert
,
A.
,
P.
Uluocak
,
R.N.
Bastos
,
D.
Mangat
,
P.
Graab
, and
U.
Gruneberg
.
2014
.
PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing
.
J. Cell Biol.
206
:
833
842
.
Espeut
,
J.
,
D.K.
Cheerambathur
,
L.
Krenning
,
K.
Oegema
, and
A.
Desai
.
2012
.
Microtubule binding by KNL-1 contributes to spindle checkpoint silencing at the kinetochore
.
J. Cell Biol.
196
:
469
482
.
Evans
,
D.R.
, and
B.A.
Hemmings
.
2000
.
Important role for phylogenetically invariant PP2Acalpha active site and C-terminal residues revealed by mutational analysis in Saccharomyces cerevisiae
.
Genetics.
156
:
21
29
.
Faesen
,
A.C.
,
M.
Thanasoula
,
S.
Maffini
,
C.
Breit
,
F.
Müller
,
S.
van Gerwen
,
T.
Bange
, and
A.
Musacchio
.
2017
.
Basis of catalytic assembly of the mitotic checkpoint complex
.
Nature.
542
:
498
502
.
Filter
,
J.J.
,
B.C.
Williams
,
M.
Eto
,
D.
Shalloway
, and
M.L.
Goldberg
.
2017
.
Unfair competition governs the interaction of pCPI-17 with myosin phosphatase (PP1-MYPT1)
.
eLife.
6
:
e24665
.
Foley
,
E.A.
,
M.
Maldonado
, and
T.M.
Kapoor
.
2011
.
Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase
.
Nat. Cell Biol.
13
:
1265
1271
.
Fontanillo
,
M.
,
I.
Zemskov
,
M.
Häfner
,
U.
Uhrig
,
F.
Salvi
,
B.
Simon
,
V.
Wittmann
, and
M.
Köhn
.
2016
.
Synthesis of Highly Selective Submicromolar Microcystin-Based Inhibitors of Protein Phosphatase (PP)2A over PP1
.
Angew. Chem. Int. Ed. Engl.
55
:
13985
13989
.
Francisco
,
L.
,
W.
Wang
, and
C.S.
Chan
.
1994
.
Type 1 protein phosphatase acts in opposition to IpL1 protein kinase in regulating yeast chromosome segregation
.
Mol. Cell. Biol.
14
:
4731
4740
.
Fujimitsu
,
K.
,
M.
Grimaldi
, and
H.
Yamano
.
2016
.
Cyclin-dependent kinase 1-dependent activation of APC/C ubiquitin ligase
.
Science.
352
:
1121
1124
.
Gharbi-Ayachi
,
A.
,
J.-C.
Labbé
,
A.
Burgess
,
S.
Vigneron
,
J.-M.
Strub
,
E.
Brioudes
,
A.
Van-Dorsselaer
,
A.
Castro
, and
T.
Lorca
.
2010
.
The substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting protein phosphatase 2A
.
Science.
330
:
1673
1677
.
Godfrey
,
M.
,
S.A.
Touati
,
M.
Kataria
,
A.
Jones
,
A.P.
Snijders
, and
F.
Uhlmann
.
2017
.
PP2ACdc55 Phosphatase Imposes Ordered Cell-Cycle Phosphorylation by Opposing Threonine Phosphorylation
.
Mol. Cell.
65
:
393
402.e3
.
Goldberg
,
J.
,
H.B.
Huang
,
Y.G.
Kwon
,
P.
Greengard
,
A.C.
Nairn
, and
J.
Kuriyan
.
1995
.
Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1
.
Nature.
376
:
745
753
.
Gong
,
C.X.
,
S.
Shaikh
,
J.Z.
Wang
,
T.
Zaidi
,
I.
Grundke-Iqbal
, and
K.
Iqbal
.
1995
.
Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain
.
J. Neurochem.
65
:
732
738
.
Goshima
,
G.
,
O.
Iwasaki
,
C.
Obuse
, and
M.
Yanagida
.
2003
.
The role of Ppe1/PP6 phosphatase for equal chromosome segregation in fission yeast kinetochore
.
EMBO J.
22
:
2752
2763
.
Grallert
,
A.
,
E.
Boke
,
A.
Hagting
,
B.
Hodgson
,
Y.
Connolly
,
J.R.
Griffiths
,
D.L.
Smith
,
J.
Pines
, and
I.M.
Hagan
.
2015
.
A PP1-PP2A phosphatase relay controls mitotic progression
.
Nature.
517
:
94
98
.
Greenwood
,
E.J.
,
N.J.
Matheson
,
K.
Wals
,
D.J.
van den Boomen
,
R.
Antrobus
,
J.C.
Williamson
, and
P.J.
Lehner
.
2016
.
Temporal proteomic analysis of HIV infection reveals remodelling of the host phosphoproteome by lentiviral Vif variants
.
eLife.
5
:
e18296
.
Griffith
,
J.P.
,
J.L.
Kim
,
E.E.
Kim
,
M.D.
Sintchak
,
J.A.
Thomson
,
M.J.
Fitzgibbon
,
M.A.
Fleming
,
P.R.
Caron
,
K.
Hsiao
, and
M.A.
Navia
.
1995
.
X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex
.
Cell.
82
:
507
522
.
Grigoriu
,
S.
,
R.
Bond
,
P.
Cossio
,
J.A.
Chen
,
N.
Ly
,
G.
Hummer
,
R.
Page
,
M.S.
Cyert
, and
W.
Peti
.
2013
.
The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin
.
PLoS Biol.
11
:
e1001492
.
Guergnon
,
J.
,
U.
Derewenda
,
J.R.
Edelson
, and
D.L.
Brautigan
.
2009
.
Mapping of protein phosphatase-6 association with its SAPS domain regulatory subunit using a model of helical repeats
.
BMC Biochem.
10
:
24
.
Haesen
,
D.
,
L.
Abbasi Asbagh
,
R.
Derua
,
A.
Hubert
,
S.
Schrauwen
,
Y.
Hoorne
,
F.
Amant
,
E.
Waelkens
,
A.
Sablina
, and
V.
Janssens
.
2016
.
Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth
.
Cancer Res.
76
:
5719
5731
.
Häfner
,
J.
,
M.I.
Mayr
,
M.M.
Möckel
, and
T.U.
Mayer
.
2014
.
Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A
.
Nat. Commun.
5
:
4397
.
Hamdan
,
F.F.
,
M.
Srour
,
J.-M.
Capo-Chichi
,
H.
Daoud
,
C.
Nassif
,
L.
Patry
,
C.
Massicotte
,
A.
Ambalavanan
,
D.
Spiegelman
,
O.
Diallo
, et al
2014
.
De novo mutations in moderate or severe intellectual disability
.
PLoS Genet.
10
:
e1004772
.
Hammond
,
D.
,
K.
Zeng
,
A.
Espert
,
R.N.
Bastos
,
R.D.
Baron
,
U.
Gruneberg
, and
F.A.
Barr
.
2013
.
Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage owing to dysregulated Aurora-A
.
J. Cell Sci.
126
:
3429
3440
.
Hattersley
,
N.
,
D.
Cheerambathur
,
M.
Moyle
,
M.
Stefanutti
,
A.
Richardson
,
K.-Y.
Lee
,
J.
Dumont
,
K.
Oegema
, and
A.
Desai
.
2016
.
A Nucleoporin Docks Protein Phosphatase 1 to Direct Meiotic Chromosome Segregation and Nuclear Assembly
.
Dev. Cell.
38
:
463
477
.
Hégarat
,
N.
,
C.
Vesely
,
P.K.
Vinod
,
C.
Ocasio
,
N.
Peter
,
J.
Gannon
,
A.W.
Oliver
,
B.
Novák
, and
H.
Hochegger
.
2014
.
PP2A/B55 and Fcp1 regulate Greatwall and Ensa dephosphorylation during mitotic exit
.
PLoS Genet.
10
:
e1004004
.
Heim
,
A.
,
A.
Konietzny
, and
T.U.
Mayer
.
2015
.
Protein phosphatase 1 is essential for Greatwall inactivation at mitotic exit
.
EMBO Rep.
16
:
1501
1510
.
Hein
,
J.B.
,
E.P.T.
Hertz
,
D.H.
Garvanska
,
T.
Kruse
, and
J.
Nilsson
.
2017
.
Distinct kinetics of serine and threonine dephosphorylation are essential for mitosis
.
Nat. Cell Biol.
19
:
1433
1440
.
Hendrickx
,
A.
,
M.
Beullens
,
H.
Ceulemans
,
T.
Den Abt
,
A.
Van Eynde
,
E.
Nicolaescu
,
B.
Lesage
, and
M.
Bollen
.
2009
.
Docking motif-guided mapping of the interactome of protein phosphatase-1
.
Chem. Biol.
16
:
365
371
.
Heroes
,
E.
,
B.
Lesage
,
J.
Görnemann
,
M.
Beullens
,
L.
Van Meervelt
, and
M.
Bollen
.
2013
.
The PP1 binding code: a molecular-lego strategy that governs specificity
.
FEBS J.
280
:
584
595
.
Hertz
,
E.P.T.
,
T.
Kruse
,
N.E.
Davey
,
B.
López-Méndez
,
J.O.
Sigurðsson
,
G.
Montoya
,
J.V.
Olsen
, and
J.
Nilsson
.
2016
.
A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase
.
Mol. Cell.
63
:
686
695
.
Hodis
,
E.
,
I.R.
Watson
,
G.V.
Kryukov
,
S.T.
Arold
,
M.
Imielinski
,
J.-P.
Theurillat
,
E.
Nickerson
,
D.
Auclair
,
L.
Li
,
C.
Place
, et al
2012
.
A landscape of driver mutations in melanoma
.
Cell.
150
:
251
263
.
Houge
,
G.
,
D.
Haesen
,
L.E.L.M.
Vissers
,
S.
Mehta
,
M.J.
Parker
,
M.
Wright
,
J.
Vogt
,
S.
McKee
,
J.L.
Tolmie
,
N.
Cordeiro
, et al
2015
.
B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability
.
J. Clin. Invest.
125
:
3051
3062
.
Huang
,
H.
,
J.
Hittle
,
F.
Zappacosta
,
R.S.
Annan
,
A.
Hershko
, and
T.J.
Yen
.
2008
.
Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit
.
J. Cell Biol.
183
:
667
680
.
Hurley
,
T.D.
,
J.
Yang
,
L.
Zhang
,
K.D.
Goodwin
,
Q.
Zou
,
M.
Cortese
,
A.K.
Dunker
, and
A.A.
DePaoli-Roach
.
2007
.
Structural basis for regulation of protein phosphatase 1 by inhibitor-2
.
J. Biol. Chem.
282
:
28874
28883
.
Janssens
,
V.
, and
J.
Goris
.
2001
.
Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling
.
Biochem. J.
353
:
417
439
.
Ji
,
Z.
,
H.
Gao
,
L.
Jia
,
B.
Li
, and
H.
Yu
.
2017
.
A sequential multi-target Mps1 phosphorylation cascade promotes spindle checkpoint signaling
.
eLife.
6
:
e22513
.
Junttila
,
M.R.
,
P.
Puustinen
,
M.
Niemelä
,
R.
Ahola
,
H.
Arnold
,
T.
Böttzauw
,
R.
Ala-aho
,
C.
Nielsen
,
J.
Ivaska
,
Y.
Taya
, et al
2007
.
CIP2A inhibits PP2A in human malignancies
.
Cell.
130
:
51
62
.
Kettenbach
,
A.N.
,
D.K.
Schweppe
,
B.K.
Faherty
,
D.
Pechenick
,
A.A.
Pletnev
, and
S.A.
Gerber
.
2011
.
Quantitative phosphoproteomics identifies substrates and functional modules of Aurora and Polo-like kinase activities in mitotic cells
.
Sci. Signal.
4
:
rs5
rs5
.
Kettenbach
,
A.N.
,
K.A.
Schlosser
,
S.P.
Lyons
,
I.
Nasa
,
J.
Gui
,
M.E.
Adamo
, and
S.A.
Gerber
.
2018
.
Global assessment of its network dynamics reveals that the kinase Plk1 inhibits the phosphatase PP6 to promote Aurora A activity
.
Sci. Signal.
11
:
eaaq1441
.
Kim
,
T.
,
P.
Lara-Gonzalez
,
B.
Prevo
,
F.
Meitinger
,
D.K.
Cheerambathur
,
K.
Oegema
, and
A.
Desai
.
2017
.
Kinetochores accelerate or delay APC/C activation by directing Cdc20 to opposing fates
.
Genes Dev.
31
:
1089
1094
.
Kim
,
Y.
,
A.J.
Holland
,
W.
Lan
, and
D.W.
Cleveland
.
2010
.
Aurora kinases and protein phosphatase 1 mediate chromosome congression through regulation of CENP-E
.
Cell.
142
:
444
455
.
Kinoshita
,
N.
,
H.
Ohkura
, and
M.
Yanagida
.
1990
.
Distinct, essential roles of type 1 and 2A protein phosphatases in the control of the fission yeast cell division cycle
.
Cell.
63
:
405
415
.
Kitajima
,
T.S.
,
T.
Sakuno
,
K.
Ishiguro
,
S.
Iemura
,
T.
Natsume
,
S.A.
Kawashima
, and
Y.
Watanabe
.
2006
.
Shugoshin collaborates with protein phosphatase 2A to protect cohesin
.
Nature.
441
:
46
52
.
Krauthammer
,
M.
,
Y.
Kong
,
B.H.
Ha
,
P.
Evans
,
A.
Bacchiocchi
,
J.P.
McCusker
,
E.
Cheng
,
M.J.
Davis
,
G.
Goh
,
M.
Choi
, et al
2012
.
Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma
.
Nat. Genet.
44
:
1006
1014
.
Krishnan
,
S.
,
A.H.
Smits
,
M.
Vermeulen
, and
D.
Reinberg
.
2017
.
Phospho-H1 Decorates the Inter-chromatid Axis and Is Evicted along with Shugoshin by SET during Mitosis
.
Mol. Cell.
67
:
579
593.e6
.
Kruse
,
T.
,
G.
Zhang
,
M.S.Y.
Larsen
,
T.
Lischetti
,
W.
Streicher
,
T.
Kragh Nielsen
,
S.P.
Bjørn
, and
J.
Nilsson
.
2013
.
Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression
.
J. Cell Sci.
126
:
1086
1092
.
Kruse
,
T.
,
N.
Biedenkopf
,
E.P.T.
Hertz
,
E.
Dietzel
,
G.
Stalmann
,
B.
López-Méndez
,
N.E.
Davey
,
J.
Nilsson
, and
S.
Becker
.
2018
.
The Ebola Virus Nucleoprotein Recruits the Host PP2A-B56 Phosphatase to Activate Transcriptional Support Activity of VP30
.
Mol. Cell.
69
:
136
145.e6
.
Krzyzosiak
,
A.
,
A.
Sigurdardottir
,
L.
Luh
,
M.
Carrara
,
I.
Das
,
K.
Schneider
, and
A.
Bertolotti
.
2018
.
Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B
.
Cell.
174
:
1216
1228.e19
.
Kumar
,
G.S.
,
E.
Gokhan
,
S.
De Munter
,
M.
Bollen
,
P.
Vagnarelli
,
W.
Peti
, and
R.
Page
.
2016
.
The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism
.
eLife.
5
:
e16539
.
Kwon
,
Y.G.
,
S.Y.
Lee
,
Y.
Choi
,
P.
Greengard
, and
A.C.
Nairn
.
1997
.
Cell cycle-dependent phosphorylation of mammalian protein phosphatase 1 by cdc2 kinase
.
Proc. Natl. Acad. Sci. USA.
94
:
2168
2173
.
Labit
,
H.
,
K.
Fujimitsu
,
N.S.
Bayin
,
T.
Takaki
,
J.
Gannon
, and
H.
Yamano
.
2012
.
Dephosphorylation of Cdc20 is required for its C-box-dependent activation of the APC/C
.
EMBO J.
31
:
3351
3362
.
Lad
,
C.
,
N.H.
Williams
, and
R.
Wolfenden
.
2003
.
The rate of hydrolysis of phosphomonoester dianions and the exceptional catalytic proficiencies of protein and inositol phosphatases
.
Proc. Natl. Acad. Sci. USA.
100
:
5607
5610
.
Lai
,
D.
,
M.
Chen
,
J.
Su
,
X.
Liu
,
K.
Rothe
,
K.
Hu
,
D.L.
Forrest
,
C.J.
Eaves
,
G.B.
Morin
, and
X.
Jiang
.
2018
.
PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL+human leukemia
.
Sci. Transl. Med.
10
:
eaan8735
.
Lara-Gonzalez
,
P.
,
F.G.
Westhorpe
, and
S.S.
Taylor
.
2012
.
The spindle assembly checkpoint
.
Curr. Biol.
22
:
R966
R980
.
Lee
,
S.J.
,
V.
Rodriguez-Bravo
,
H.
Kim
,
S.
Datta
, and
E.A.
Foley
.
2017
.
The PP2AB56 phosphatase promotes the association of Cdc20 with APC/C in mitosis
.
J. Cell Sci.
130
:
1760
1771
.
Li
,
M.
,
A.
Makkinje
, and
Z.
Damuni
.
1996
.
The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A
.
J. Biol. Chem.
271
:
11059
11062
.
Li
,
X.
,
M.
Wilmanns
,
J.
Thornton
, and
M.
Köhn
.
2013
.
Elucidating human phosphatase-substrate networks
.
Sci. Signal.
6
:
rs10
rs10
.
Lindqvist
,
A.
,
V.
Rodríguez-Bravo
, and
R.H.
Medema
.
2009
.
The decision to enter mitosis: feedback and redundancy in the mitotic entry network
.
J. Cell Biol.
185
:
193
202
.
Liu
,
D.
,
M.
Vleugel
,
C.B.
Backer
,
T.
Hori
,
T.
Fukagawa
,
I.M.
Cheeseman
, and
M.A.
Lampson
.
2010
.
Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase
.
J. Cell Biol.
188
:
809
820
.
London
,
N.
,
S.
Ceto
,
J.A.
Ranish
, and
S.
Biggins
.
2012
.
Phosphoregulation of Spc105 by Mps1 and PP1 Regulates Bub1 Localization to Kinetochores
.
Curr. Biol.
22
:
900
906
.
Longin
,
S.
,
K.
Zwaenepoel
,
J.V.
Louis
,
S.
Dilworth
,
J.
Goris
, and
V.
Janssens
.
2007
.
Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic Subunit
.
J. Biol. Chem.
282
:
26971
26980
.
Luke
,
M.M.
,
F.
Della Seta
,
C.J.
Di Como
,
H.
Sugimoto
,
R.
Kobayashi
, and
K.T.
Arndt
.
1996
.
The SAP, a new family of proteins, associate and function positively with the SIT4 phosphatase
.
Mol. Cell. Biol.
16
:
2744
2755
.
Ma
,
L.
,
Y.
Bayram
,
H.M.
McLaughlin
,
M.T.
Cho
,
A.
Krokosky
,
C.E.
Turner
,
K.
Lindstrom
,
C.P.
Bupp
,
K.
Mayberry
,
W.
Mu
, et al
2016
a
.
De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease
.
Hum. Genet.
135
:
1399
1409
.
Ma
,
S.
,
S.
Vigneron
,
P.
Robert
,
J.-M.
Strub
,
S.
Cianferani
,
A.
Castro
, and
T.
Lorca
.
2016
b
.
Greatwall dephosphorylation and inactivation upon mitotic exit is triggered by PP1
.
J. Cell Sci.
129
:
1329
1339
.
Manchado
,
E.
,
M.
Guillamot
,
G.
de Cárcer
,
M.
Eguren
,
M.
Trickey
,
I.
García-Higuera
,
S.
Moreno
,
H.
Yamano
,
M.
Cañamero
, and
M.
Malumbres
.
2010
.
Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase
.
Cancer Cell.
18
:
641
654
.
Manning
,
G.
,
D.B.
Whyte
,
R.
Martinez
,
T.
Hunter
, and
S.
Sudarsanam
.
2002
.
The protein kinase complement of the human genome
.
Science.
298
:
1912
1934
.
Mao
,
X.
,
L.K.
Boyd
,
R.J.
Yáñez-Muñoz
,
T.
Chaplin
,
L.
Xue
,
D.
Lin
,
L.
Shan
,
D.M.
Berney
,
B.D.
Young
, and
Y.-J.
Lu
.
2011
.
Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer
.
Am. J. Cancer Res.
1
:
604
617
.
Marsh
,
J.A.
,
B.
Dancheck
,
M.J.
Ragusa
,
M.
Allaire
,
J.D.
Forman-Kay
, and
W.
Peti
.
2010
.
Structural diversity in free and bound states of intrinsically disordered protein phosphatase 1 regulators
.
Structure.
18
:
1094
1103
.
Matsumura
,
F.
,
Y.
Yamakita
, and
S.
Yamashiro
.
2011
.
Myosin phosphatase-targeting subunit 1 controls chromatid segregation
.
J. Biol. Chem.
286
:
10825
10833
.
Mayer-Jaekel
,
R.E.
,
H.
Ohkura
,
R.
Gomes
,
C.E.
Sunkel
,
S.
Baumgartner
,
B.A.
Hemmings
, and
D.M.
Glover
.
1993
.
The 55 kd regulatory subunit of Drosophila protein phosphatase 2A is required for anaphase
.
Cell.
72
:
621
633
.
McClinch
,
K.
,
R.A.
Avelar
,
D.
Callejas
,
S.
Izadmehr
,
D.
Wiredja
,
A.
Perl
,
J.
Sangodkar
,
D.B.
Kastrinsky
,
D.
Schlatzer
,
M.
Cooper
, et al
2018
.
Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer
.
Cancer Res.
78
:
2065
2080
.
McCloy
,
R.A.
,
B.L.
Parker
,
S.
Rogers
,
R.
Chaudhuri
,
V.
Gayevskiy
,
N.J.
Hoffman
,
N.
Ali
,
D.N.
Watkins
,
R.J.
Daly
,
D.E.
James
, et al
2015
.
Global Phosphoproteomic Mapping of Early Mitotic Exit in Human Cells Identifies Novel Substrate Dephosphorylation Motifs
.
Mol. Cell. Proteomics.
14
:
2194
2212
.
Meadows
,
J.C.
,
L.A.
Shepperd
,
V.
Vanoosthuyse
,
T.C.
Lancaster
,
A.M.
Sochaj
,
G.J.
Buttrick
,
K.G.
Hardwick
, and
J.B.A.
Millar
.
2011
.
Spindle checkpoint silencing requires association of PP1 to both Spc7 and kinesin-8 motors
.
Dev. Cell.
20
:
739
750
.
Meiselbach
,
H.
,
H.
Sticht
, and
R.
Enz
.
2006
.
Structural analysis of the protein phosphatase 1 docking motif: molecular description of binding specificities identifies interacting proteins
.
Chem. Biol.
13
:
49
59
.
Meppelink
,
A.
,
L.
Kabeche
,
M.J.M.
Vromans
,
D.A.
Compton
, and
S.M.A.
Lens
.
2015
.
Shugoshin-1 balances Aurora B kinase activity via PP2A to promote chromosome bi-orientation
.
Cell Reports.
11
:
508
515
.
Mochida
,
S.
2014
.
Regulation of α-endosulfine, an inhibitor of protein phosphatase 2A, by multisite phosphorylation
.
FEBS J.
281
:
1159
1169
.
Mochida
,
S.
, and
T.
Hunt
.
2007
.
Calcineurin is required to release Xenopus egg extracts from meiotic M phase
.
Nature.
449
:
336
340
.
Mochida
,
S.
,
S.
Ikeo
,
J.
Gannon
, and
T.
Hunt
.
2009
.
Regulated activity of PP2A-B55 delta is crucial for controlling entry into and exit from mitosis in Xenopus egg extracts
.
EMBO J.
28
:
2777
2785
.
Mochida
,
S.
,
S.L.
Maslen
,
M.
Skehel
, and
T.
Hunt
.
2010
.
Greatwall phosphorylates an inhibitor of protein phosphatase 2A that is essential for mitosis
.
Science.
330
:
1670
1673
.
Moorhead
,
G.B.G.
,
L.
Trinkle-Mulcahy
, and
A.
Ulke-Lemée
.
2007
.
Emerging roles of nuclear protein phosphatases
.
Nat. Rev. Mol. Cell Biol.
8
:
234
244
.
Moorhead
,
G.B.G.
,
L.
Trinkle-Mulcahy
,
M.
Nimick
,
V.
De Wever
,
D.G.
Campbell
,
R.
Gourlay
,
Y.W.
Lam
, and
A.I.
Lamond
.
2008
.
Displacement affinity chromatography of protein phosphatase one (PP1) complexes
.
BMC Biochem.
9
:
28
.
Morin
,
V.
,
S.
Prieto
,
S.
Melines
,
S.
Hem
,
M.
Rossignol
,
T.
Lorca
,
J.
Espeut
,
N.
Morin
, and
A.
Abrieu
.
2012
.
CDK-dependent potentiation of MPS1 kinase activity is essential to the mitotic checkpoint
.
Curr. Biol.
22
:
289
295
.
Mosavi
,
L.K.
,
T.J.
Cammett
,
D.C.
Desrosiers
, and
Z.-Y.
Peng
.
2004
.
The ankyrin repeat as molecular architecture for protein recognition
.
Protein Sci.
13
:
1435
1448
.
Mumby
,
M.
2007
.
PP2A: unveiling a reluctant tumor suppressor
.
Cell.
130
:
21
24
.
Nasa
,
I.
,
S.F.
Rusin
,
A.N.
Kettenbach
, and
G.B.
Moorhead
.
2018
.
Aurora B opposes PP1 function in mitosis by phosphorylating the conserved PP1-binding RVxF motif in PP1 regulatory proteins
.
Sci. Signal.
11
:
eaai8669
.
Nijenhuis
,
W.
,
G.
Vallardi
,
A.
Teixeira
,
G.J.P.L.
Kops
, and
A.T.
Saurin
.
2014
.
Negative feedback at kinetochores underlies a responsive spindle checkpoint signal
.
Nat. Cell Biol.
16
:
1257
1264
.
Nobumori
,
Y.
,
G.P.
Shouse
,
L.
Fan
, and
X.
Liu
.
2012
.
HEAT repeat 1 motif is required for B56γ-containing protein phosphatase 2A (B56γ-PP2A) holoenzyme assembly and tumor-suppressive function
.
J. Biol. Chem.
287
:
11030
11036
.
Oberoi
,
J.
,
D.M.
Dunn
,
M.R.
Woodford
,
L.
Mariotti
,
J.
Schulman
,
D.
Bourboulia
,
M.
Mollapour
, and
C.K.
Vaughan
.
2016
.
Structural and functional basis of protein phosphatase 5 substrate specificity
.
Proc. Natl. Acad. Sci. USA.
113
:
9009
9014
.
Ohkura
,
H.
, and
M.
Yanagida
.
1991
.
S. pombe gene sds22+ essential for a midmitotic transition encodes a leucine-rich repeat protein that positively modulates protein phosphatase-1
.
Cell.
64
:
149
157
.
Ohkura
,
H.
,
Y.
Adachi
,
N.
Kinoshita
,
O.
Niwa
,
T.
Toda
, and
M.
Yanagida
.
1988
.
Cold-sensitive and caffeine-supersensitive mutants of the Schizosaccharomyces pombe dis genes implicated in sister chromatid separation during mitosis
.
EMBO J.
7
:
1465
1473
.
Olsen
,
J.V.
,
M.
Vermeulen
,
A.
Santamaria
,
C.
Kumar
,
M.L.
Miller
,
L.J.
Jensen
,
F.
Gnad
,
J.
Cox
,
T.S.
Jensen
,
E.A.
Nigg
, et al
2010
.
Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis
.
Sci. Signal.
3
:
ra3
ra3
.
Peggie
,
M.W.
,
S.H.
MacKelvie
,
A.
Bloecher
,
E.V.
Knatko
,
K.
Tatchell
, and
M.J.R.
Stark
.
2002
.
Essential functions of Sds22p in chromosome stability and nuclear localization of PP1
.
J. Cell Sci.
115
:
195
206
.
Peti
,
W.
,
A.C.
Nairn
, and
R.
Page
.
2013
.
Structural basis for protein phosphatase 1 regulation and specificity
.
FEBS J.
280
:
596
611
.
Petrone
,
A.
,
M.E.
Adamo
,
C.
Cheng
, and
A.N.
Kettenbach
.
2016
.
Identification of Candidate Cyclin-dependent kinase 1 (Cdk1) Substrates in Mitosis by Quantitative Phosphoproteomics
.
Mol. Cell. Proteomics.
15
:
2448
2461
.
Pines
,
J.
2011
.
Cubism and the cell cycle: the many faces of the APC/C
.
Nat. Rev. Mol. Cell Biol.
12
:
427
438
.
Pinna
,
L.A.
,
A.
Donella
,
G.
Clari
, and
V.
Moret
.
1976
.
Preferential dephosphorylation of protein bound phosphorylthreonine and phosphorylserine residues by cytosol and mitochondrial “casein phosphatases”
.
Biochem. Biophys. Res. Commun.
70
:
1308
1315
.
Porter
,
I.M.
,
K.
Schleicher
,
M.
Porter
, and
J.R.
Swedlow
.
2013
.
Bod1 regulates protein phosphatase 2A at mitotic kinetochores
.
Nat. Commun.
4
:
2677
.
Posch
,
M.
,
G.A.
Khoudoli
,
S.
Swift
,
E.M.
King
,
J.G.
Deluca
, and
J.R.
Swedlow
.
2010
.
Sds22 regulates aurora B activity and microtubule-kinetochore interactions at mitosis
.
J. Cell Biol.
191
:
61
74
.
Prescott
,
D.M.
, and
M.A.
Bender
.
1962
.
Synthesis of RNA and protein during mitosis in mammalian tissue culture cells
.
Exp. Cell Res.
26
:
260
268
.
Puntoni
,
F.
, and
E.
Villa-Moruzzi
.
1995
.
Phosphorylation of the inhibitor-2 of protein phosphatase-1 by cdc2-cyclin B and GSK3
.
Biochem. Biophys. Res. Commun.
207
:
732
739
.
Qian
,
J.
,
M.
Beullens
,
B.
Lesage
, and
M.
Bollen
.
2013
.
Aurora B defines its own chromosomal targeting by opposing the recruitment of the phosphatase scaffold Repo-Man
.
Curr. Biol.
23
:
1136
1143
.
Qian
,
J.
,
M.
Beullens
,
J.
Huang
,
S.
De Munter
,
B.
Lesage
, and
M.
Bollen
.
2015
.
Cdk1 orders mitotic events through coordination of a chromosome-associated phosphatase switch
.
Nat. Commun.
6
:
10215
.
Qian
,
J.
,
M.A.
García-Gimeno
,
M.
Beullens
,
M.G.
Manzione
,
G.
Van der Hoeven
,
J.C.
Igual
,
M.
Heredia
,
P.
Sanz
,
L.
Gelens
, and
M.
Bollen
.
2017
.
An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint
.
Mol. Cell.
68
:
715
730.e5
.
Qiao
,
R.
,
F.
Weissmann
,
M.
Yamaguchi
,
N.G.
Brown
,
R.
VanderLinden
,
R.
Imre
,
M.A.
Jarvis
,
M.R.
Brunner
,
I.F.
Davidson
,
G.
Litos
, et al
2016
.
Mechanism of APC/CCDC20 activation by mitotic phosphorylation
.
Proc. Natl. Acad. Sci. USA.
113
:
E2570
E2578
.
Ragusa
,
M.J.
,
B.
Dancheck
,
D.A.
Critton
,
A.C.
Nairn
,
R.
Page
, and
W.
Peti
.
2010
.
Spinophilin directs protein phosphatase 1 specificity by blocking substrate binding sites
.
Nat. Struct. Mol. Biol.
17
:
459
464
.
Ren
,
D.
,
L.A.
Fisher
,
J.
Zhao
,
L.
Wang
,
B.C.
Williams
,
M.L.
Goldberg
, and
A.
Peng
.
2017
.
Cell cycle-dependent regulation of Greatwall kinase by protein phosphatase 1 and regulatory subunit 3B
.
J. Biol. Chem.
292
:
10026
10034
.
Rodrigues
,
N.T.L.
,
S.
Lekomtsev
,
S.
Jananji
,
J.
Kriston-Vizi
,
G.R.X.
Hickson
, and
B.
Baum
.
2015
.
Kinetochore-localized PP1-Sds22 couples chromosome segregation to polar relaxation
.
Nature.
524
:
489
492
.
Rogers
,
S.
,
D.
Fey
,
R.A.
McCloy
,
B.L.
Parker
,
N.J.
Mitchell
,
R.J.
Payne
,
R.J.
Daly
,
D.E.
James
,
C.E.
Caldon
,
D.N.
Watkins
, et al
2016
.
PP1 initiates the dephosphorylation of MASTL, triggering mitotic exit and bistability in human cells
.
J. Cell Sci.
129
:
1340
1354
.
Rosenberg
,
J.S.
,
F.R.
Cross
, and
H.
Funabiki
.
2011
.
KNL1/Spc105 recruits PP1 to silence the spindle assembly checkpoint
.
Curr. Biol.
21
:
942
947
.
Rusin
,
S.F.
,
K.A.
Schlosser
,
M.E.
Adamo
, and
A.N.
Kettenbach
.
2015
.
Quantitative phosphoproteomics reveals new roles for the protein phosphatase PP6 in mitotic cells
.
Sci. Signal.
8
:
rs12
rs12
.
Rusin
,
S.F.
,
M.E.
Adamo
, and
A.N.
Kettenbach
.
2017
.
Identification of Candidate Casein Kinase 2 Substrates in Mitosis by Quantitative Phosphoproteomics
.
Front. Cell Dev. Biol.
5
:
97
.
Sablina
,
A.A.
,
W.
Chen
,
J.D.
Arroyo
,
L.
Corral
,
M.
Hector
,
S.E.
Bulmer
,
J.A.
DeCaprio
, and
W.C.
Hahn
.
2007
.
The tumor suppressor PP2A Abeta regulates the RalA GTPase
.
Cell.
129
:
969
982
.
Saha
,
P.
,
Q.
Eichbaum
,
E.D.
Silberman
,
B.J.
Mayer
, and
A.
Dutta
.
1997
.
p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases
.
Mol. Cell. Biol.
17
:
4338
4345
.
Santamaria
,
A.
,
B.
Wang
,
S.
Elowe
,
R.
Malik
,
F.
Zhang
,
M.
Bauer
,
A.
Schmidt
,
H.H.W.
Silljé
,
R.
Körner
, and
E.A.
Nigg
.
2011
.
The Plk1-dependent phosphoproteome of the early mitotic spindle
.
Mol. Cell. Proteomics.
10
:
M110.004457
.
Schmitz
,
M.H.A.
,
M.
Held
,
V.
Janssens
,
J.R.A.
Hutchins
,
O.
Hudecz
,
E.
Ivanova
,
J.
Goris
,
L.
Trinkle-Mulcahy
,
A.I.
Lamond
,
I.
Poser
, et al
2010
.
Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells
.
Nat. Cell Biol.
12
:
886
893
.
Schott
,
K.
,
N.V.
Fuchs
,
R.
Derua
,
B.
Mahboubi
,
E.
Schnellbächer
,
J.
Seifried
,
C.
Tondera
,
H.
Schmitz
,
C.
Shepard
,
A.
Brandariz-Nuñez
, et al
2018
.
Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit
.
Nat. Commun.
9
:
2227
.
Shepperd
,
L.A.
,
J.C.
Meadows
,
A.M.
Sochaj
,
T.C.
Lancaster
,
J.
Zou
,
G.J.
Buttrick
,
J.
Rappsilber
,
K.G.
Hardwick
, and
J.B.A.
Millar
.
2012
.
Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint
.
Curr. Biol.
22
:
891
899
.
Shi
,
Y.
2009
.
Serine/threonine phosphatases: mechanism through structure
.
Cell.
139
:
468
484
.
Shimanuki
,
M.
,
N.
Kinoshita
,
H.
Ohkura
,
T.
Yoshida
,
T.
Toda
, and
M.
Yanagida
.
1993
.
Isolation and characterization of the fission yeast protein phosphatase gene ppe1+ involved in cell shape control and mitosis
.
Mol. Biol. Cell.
4
:
303
313
.
Sivakumar
,
S.
,
P.Ł.
Janczyk
,
Q.
Qu
,
C.A.
Brautigam
,
P.T.
Stukenberg
,
H.
Yu
, and
G.J.
Gorbsky
.
2016
.
The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores
.
eLife.
5
:
e12902
.
Skoufias
,
D.A.
,
R.-L.
Indorato
,
F.
Lacroix
,
A.
Panopoulos
, and
R.L.
Margolis
.
2007
.
Mitosis persists in the absence of Cdk1 activity when proteolysis or protein phosphatase activity is suppressed
.
J. Cell Biol.
179
:
671
685
.
Stefansson
,
B.
,
T.
Ohama
,
A.E.
Daugherty
, and
D.L.
Brautigan
.
2008
.
Protein phosphatase 6 regulatory subunits composed of ankyrin repeat domains
.
Biochemistry.
47
:
1442
1451
.
Stegmeier
,
F.
, and
A.
Amon
.
2004
.
Closing mitosis: the functions of the Cdc14 phosphatase and its regulation
.
Annu. Rev. Genet.
38
:
203
232
.
Suijkerbuijk
,
S.J.E.
,
M.
Vleugel
,
A.
Teixeira
, and
G.J.P.L.
Kops
.
2012
.
Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments
.
Dev. Cell.
23
:
745
755
.
Swingle
,
M.R.
,
R.E.
Honkanen
, and
E.M.
Ciszak
.
2004
.
Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5
.
J. Biol. Chem.
279
:
33992
33999
.
Tang
,
Z.
,
H.
Shu
,
W.
Qi
,
N.A.
Mahmood
,
M.C.
Mumby
, and
H.
Yu
.
2006
.
PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation
.
Dev. Cell.
10
:
575
585
.
Taylor
,
J.H.
1960
.
Nucleic acid synthesis in relation to the cell division cycle
.
Ann. N. Y. Acad. Sci.
90
:
409
421
.
Terrak
,
M.
,
F.
Kerff
,
K.
Langsetmo
,
T.
Tao
, and
R.
Dominguez
.
2004
.
Structural basis of protein phosphatase 1 regulation
.
Nature.
429
:
780
784
.
Tompa
,
P.
,
N.E.
Davey
,
T.J.
Gibson
, and
M.M.
Babu
.
2014
.
A million peptide motifs for the molecular biologist
.
Mol. Cell.
55
:
161
169
.
Trinkle-Mulcahy
,
L.
,
P.D.
Andrews
,
S.
Wickramasinghe
,
J.
Sleeman
,
A.
Prescott
,
Y.W.
Lam
,
C.
Lyon
,
J.R.
Swedlow
, and
A.I.
Lamond
.
2003
.
Time-lapse imaging reveals dynamic relocalization of PP1gamma throughout the mammalian cell cycle
.
Mol. Biol. Cell.
14
:
107
117
.
Trinkle-Mulcahy
,
L.
,
J.
Andersen
,
Y.W.
Lam
,
G.
Moorhead
,
M.
Mann
, and
A.I.
Lamond
.
2006
.
Repo-Man recruits PP1 gamma to chromatin and is essential for cell viability
.
J. Cell Biol.
172
:
679
692
.
Tung
,
H.Y.
,
W.
Wang
, and
C.S.
Chan
.
1995
.
Regulation of chromosome segregation by Glc8p, a structural homolog of mammalian inhibitor 2 that functions as both an activator and an inhibitor of yeast protein phosphatase 1
.
Mol. Cell. Biol.
15
:
6064
6074
.
Vagnarelli
,
P.
,
S.
Ribeiro
,
L.
Sennels
,
L.
Sanchez-Pulido
,
F.
de Lima Alves
,
T.
Verheyen
,
D.A.
Kelly
,
C.P.
Ponting
,
J.
Rappsilber
, and
W.C.
Earnshaw
.
2011
.
Repo-Man coordinates chromosomal reorganization with nuclear envelope reassembly during mitotic exit
.
Dev. Cell.
21
:
328
342
.
Vázquez-Novelle
,
M.D.
,
L.
Sansregret
,
A.E.
Dick
,
C.A.
Smith
,
A.D.
McAinsh
,
D.W.
Gerlich
, and
M.
Petronczki
.
2014
.
Cdk1 inactivation terminates mitotic checkpoint surveillance and stabilizes kinetochore attachments in anaphase
.
Curr. Biol.
24
:
638
645
.
Vigneron
,
S.
,
E.
Brioudes
,
A.
Burgess
,
J.-C.
Labbé
,
T.
Lorca
, and
A.
Castro
.
2009
.
Greatwall maintains mitosis through regulation of PP2A
.
EMBO J.
28
:
2786
2793
.
Vigneron
,
S.
,
A.
Gharbi-Ayachi
,
A.-A.
Raymond
,
A.
Burgess
,
J.-C.
Labbé
,
G.
Labesse
,
B.
Monsarrat
,
T.
Lorca
, and
A.
Castro
.
2011
.
Characterization of the mechanisms controlling Greatwall activity
.
Mol. Cell. Biol.
31
:
2262
2275
.
Villa-Moruzzi
,
E.
1992
.
Activation of type-1 protein phosphatase by cdc2 kinase
.
FEBS Lett.
304
:
211
215
.
Visconti
,
R.
,
L.
Palazzo
,
R.
Della Monica
, and
D.
Grieco
.
2012
.
Fcp1-dependent dephosphorylation is required for M-phase-promoting factor inactivation at mitosis exit
.
Nat. Commun.
3
:
894
.
Wakula
,
P.
,
M.
Beullens
,
H.
Ceulemans
,
W.
Stalmans
, and
M.
Bollen
.
2003
.
Degeneracy and function of the ubiquitous RVXF motif that mediates binding to protein phosphatase-1
.
J. Biol. Chem.
278
:
18817
18823
.
Wang
,
J.
,
Z.
Wang
,
T.
Yu
,
H.
Yang
,
D.M.
Virshup
,
G.J.P.L.
Kops
,
S.H.
Lee
,
W.
Zhou
,
X.
Li
,
W.
Xu
, and
Z.
Rao
.
2016
a
.
Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization
.
Protein Cell.
7
:
516
526
.
Wang
,
W.
,
P.T.
Stukenberg
, and
D.L.
Brautigan
.
2008
.
Phosphatase inhibitor-2 balances protein phosphatase 1 and aurora B kinase for chromosome segregation and cytokinesis in human retinal epithelial cells
.
Mol. Biol. Cell.
19
:
4852
4862
.
Wang
,
X.
,
R.
Bajaj
,
M.
Bollen
,
W.
Peti
, and
R.
Page
.
2016
b
.
Expanding the PP2A Interactome by Defining a B56-Specific SLiM
.
Structure.
24
:
2174
2181
.
Williams
,
B.C.
,
J.J.
Filter
,
K.A.
Blake-Hodek
,
B.E.
Wadzinski
,
N.J.
Fuda
,
D.
Shalloway
, and
M.L.
Goldberg
.
2014
.
Greatwall-phosphorylated Endosulfine is both an inhibitor and a substrate of PP2A-B55 heterotrimers
.
eLife.
3
:
e01695
.
Wu
,
C.-G.
,
H.
Chen
,
F.
Guo
,
V.K.
Yadav
,
S.J.
Mcilwain
,
M.
Rowse
,
A.
Choudhary
,
Z.
Lin
,
Y.
Li
,
T.
Gu
, et al
2017
.
PP2A-B’ holoenzyme substrate recognition, regulation and role in cytokinesis
.
Cell Discov.
3
:
17027
.
Wu
,
J.Q.
,
J.Y.
Guo
,
W.
Tang
,
C.-S.
Yang
,
C.D.
Freel
,
C.
Chen
,
A.C.
Nairn
, and
S.
Kornbluth
.
2009
.
PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation
.
Nat. Cell Biol.
11
:
644
651
.
Wurzenberger
,
C.
,
M.
Held
,
M.A.
Lampson
,
I.
Poser
,
A.A.
Hyman
, and
D.W.
Gerlich
.
2012
.
Sds22 and Repo-Man stabilize chromosome segregation by counteracting Aurora B on anaphase kinetochores
.
J. Cell Biol.
198
:
173
183
.
Xu
,
P.
,
E.A.
Raetz
,
M.
Kitagawa
,
D.M.
Virshup
, and
S.H.
Lee
.
2013
.
BUBR1 recruits PP2A via the B56 family of targeting subunits to promote chromosome congression
.
Biol. Open.
2
:
479
486
.
Xu
,
Y.
,
Y.
Xing
,
Y.
Chen
,
Y.
Chao
,
Z.
Lin
,
E.
Fan
,
J.W.
Yu
,
S.
Strack
,
P.D.
Jeffrey
, and
Y.
Shi
.
2006
.
Structure of the protein phosphatase 2A holoenzyme
.
Cell.
127
:
1239
1251
.
Xu
,
Y.
,
Y.
Chen
,
P.
Zhang
,
P.D.
Jeffrey
, and
Y.
Shi
.
2008
.
Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation
.
Mol. Cell.
31
:
873
885
.
Xu
,
Z.
,
B.
Cetin
,
M.
Anger
,
U.S.
Cho
,
W.
Helmhart
,
K.
Nasmyth
, and
W.
Xu
.
2009
.
Structure and function of the PP2A-shugoshin interaction
.
Mol. Cell.
35
:
426
441
.
Yamagishi
,
Y.
,
C.-H.
Yang
,
Y.
Tanno
, and
Y.
Watanabe
.
2012
.
MPS1/Mph1 phosphorylates the kinetochore protein KNL1/Spc7 to recruit SAC components
.
Nat. Cell Biol.
14
:
746
752
.
Yamashiro
,
S.
,
Y.
Yamakita
,
G.
Totsukawa
,
H.
Goto
,
K.
Kaibuchi
,
M.
Ito
,
D.J.
Hartshorne
, and
F.
Matsumura
.
2008
.
Myosin phosphatase-targeting subunit 1 regulates mitosis by antagonizing polo-like kinase 1
.
Dev. Cell.
14
:
787
797
.
York
,
A.
,
E.C.
Hutchinson
, and
E.
Fodor
.
2014
.
Interactome analysis of the influenza A virus transcription/replication machinery identifies protein phosphatase 6 as a cellular factor required for efficient virus replication
.
J. Virol.
88
:
13284
13299
.
Zeng
,
K.
,
R.N.
Bastos
,
F.A.
Barr
, and
U.
Gruneberg
.
2010
.
Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2
.
J. Cell Biol.
191
:
1315
1332
.
Zhang
,
L.
, and
E.Y.
Lee
.
1997
.
Mutational analysis of substrate recognition by protein phosphatase 1
.
Biochemistry.
36
:
8209
8214
.
Zhang
,
G.
,
T.
Lischetti
, and
J.
Nilsson
.
2014
.
A minimal number of MELT repeats supports all the functions of KNL1 in chromosome segregation
.
J. Cell Sci.
127
:
871
884
.
Zhang
,
G.
,
T.
Kruse
,
B.
López-Méndez
,
K.B.
Sylvestersen
,
D.H.
Garvanska
,
S.
Schopper
,
M.L.
Nielsen
, and
J.
Nilsson
.
2017
.
Bub1 positions Mad1 close to KNL1 MELT repeats to promote checkpoint signalling
.
Nat. Commun.
8
:
15822
.
Zhang
,
J.
,
Z.
Zhang
,
K.
Brew
, and
E.Y.
Lee
.
1996
.
Mutational analysis of the catalytic subunit of muscle protein phosphatase-1
.
Biochemistry.
35
:
6276
6282
.
Zhang
,
L.
,
H.
Zhou
,
X.
Li
,
R.L.
Vartuli
,
M.
Rowse
,
Y.
Xing
,
P.
Rudra
,
D.
Ghosh
,
R.
Zhao
, and
H.L.
Ford
.
2018
.
Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression
.
Nat. Commun.
9
:
1047
.
Zhang
,
S.
,
L.
Chang
,
C.
Alfieri
,
Z.
Zhang
,
J.
Yang
,
S.
Maslen
,
M.
Skehel
, and
D.
Barford
.
2016
.
Molecular mechanism of APC/C activation by mitotic phosphorylation
.
Nature.
533
:
260
264
.
Zhou
,
X.
,
B.L.
Updegraff
,
Y.
Guo
,
M.
Peyton
,
L.
Girard
,
J.E.
Larsen
,
X.-J.
Xie
,
Y.
Zhou
,
T.H.
Hwang
,
Y.
Xie
, et al
2017
.
PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis
.
Cancer Res.
77
:
187
197
.
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