Monopolar Spindle 1 (Mps1)
Mps1 was first identified in the budding yeast Saccharomyces cerevisiae and named for the monopolar spindles that form in the mps1 mutant strain (reviewed in Fisk et al. 2004). These spindles are generated as a result of the absence of spindle pole body (SPB) duplication; mutant yeast cells consequently undergo a “monopolar” mitosis. Four years later, the mps1 gene was shown to encode an essential dual-specificity protein kinase, and a fission yeast homolog, termed Mph1, was also identified in Schizosaccharomyces pombe (Fisk et al. 2004). Library screening with antibodies to phosphotyrosine also identified a human protein kinase termed TTK/PYT, and a mouse kinase termed Esk; these were later recognized as vertebrate Mps1 orthologs. In addition, Xenopus, zebrafish and Drosophila Mps1 orthologs have also been characterized (Fisk et al. 2004). Indeed, the Mps1 family of protein kinases has now recognized in all eukaryotic phyla for which sequence data exist, except in the Caenorhabditis elegans genome, where its function may be redundant or replaced by a distinct protein kinase (Winey and Huneycutt 2002; Fisk et al. 2004).
Functions of Mps1
Furthermore, Mps1p localizes to SPBs (Fisk et al. 2004), and chemical genetic-induced inactivation of Mps1 revealed a defect in SPB duplication, suggesting that Mps1 has an important role in this process (Jones et al. 2005). Mps1p regulates SPB duplication by phosphorylating SPB components, including Spc98p, Spc110p, Spc42p, and Spc29p, which are all substrates of Mps1p in vitro and in vivo (Winey and Huneycutt 2002; Holinger et al. 2009; Fig. 2). Recently, the phosphorylation of Spc29p in G1/S phase was suggested to be required for recruiting the SPB membrane insertion machinery complex Mps2-Bbp1 to the newly formed SPB to facilitate its insertion into the nuclear envelope (Araki et al. 2010). An additional Mps1 substrate, the yeast centrin Cdc31, was also identified and its phosphorylation was shown to regulate its binding to the essential half bridge protein Kar1 (Araki et al. 2010). Although Mps1p is essential for SPB duplication in budding yeast, the fission yeast S. pombe Mps1 ortholog, Mph1, does not seem to have such a function (Winey and Huneycutt 2002).
The well-characterized requirement for Mps1p in SPB duplication in budding yeast implies that vertebrate Mps1 proteins might also function in centrosome duplication, analogous to those described for yeast Ipl (Aurora) and vertebrate Cdc5 (Polo) kinases. The mouse Mps1 enzyme was the first vertebrate Mps1 shown to regulate centrosome duplication. Mouse Mps1 localizes to the centrosome throughout the cell cycle in NIH 3T3 cells, and its overexpression induces centrosome reduplication, whereas overexpression of a catalytically inactive mutant (D637A) prevents centrosome duplication (reviewed in Fisk et al. 2004). Conflicting data have been reported as to the localization of human Mps1 and its possible roles in centrosome duplication. Stucke et al. demonstrated that human Mps1 is not required for centrosome duplication (Stucke et al. 2002), and did not find localization of human Mps1 at centrosomes or evidence that the kinase has a role in the centrosome cycle, despite the use of various functional analyses, including antibody microinjection, small interfering RNA (siRNA), and overexpression of wild-type and kinase-dead human Mps1. This result was unexpected owing to the very high sequence similarity (90%) between the mouse and human Mps1 proteins (Winey and Huneycutt 2002; Fisk et al. 2003). In contrast, separate studies showed that human Mps1 does localize to centrosomes during interphase using distinct polyclonal Mps1 antibodies (reviewed in Fisk et al. 2004). Tyler et al. (2009) also reported centrosomal localization of phosphorylated human Mps1 in mitotic HeLa and DLD1 cells using RNA interference (RNAi)-validated phosphospecific antibodies. Moreover, Fisk et al. showed that overexpression of human Mps1 causes centrosome reduplication, whereas overexpression of a kinase-dead mutant or siRNA depletion prevents normal centrosome duplication in various cell types, including NIH 3T3 cells (Fisk et al. 2003). Additional data further suggested that Mps1-dependent centrosome duplication lies downstream of Cyclin-Dependent Kinase-2 (CDK2) (Kasbek et al. 2007, 2009). Mps1-associated acceleration of centrosome duplication may also depend on the presence of phosphorylated mortalin (Kanai et al. 2007). Thus, despite controversy, vertebrate Mps1 protein kinases – including the human ortholog – do seem to regulate aspects of centrosome duplication.
The role of Mps1 in the SAC has been studied extensively. The checkpoint function of Mps1 was first reported when mutant mps1-1 yeast cells were shown to inappropriately segregate their DNA (Fisk et al. 2004). The mps1-1 mutant also overrides a nocodazole-induced mitotic checkpoint, further suggesting that Mps1p is essential in the SAC (Fisk et al. 2004). Mps1 localizes to the kinetochore through a complex series of protein-substrate interactions involving kinetochore components such as Mad1p, Ndc80-Hec1, and CENP-E (Fisk et al. 2004; Vigneron et al. 2004; Zhao and Chen 2006; Tighe et al. 2008). Notably, Mps1 also interacts with the APC and is destabilized by APC/C-Cdc20 for mitosis exit after anaphase in budding yeast (Palframan et al. 2006) and in human cells (Cui et al. 2010).
A chemical genetic study clearly revealed that inactivation of yeast Mps1 generates defects in the SAC (Jones et al. 2005). Moreover, the small-molecule inhibitor cincreasin blocks this checkpoint by inhibiting Mps1p (Dorer et al. 2005). The localization of Mps1p to kinetochores, observed by immunofluorescence and immunoelectron microscopy, is also consistent with its function in the SAC (Winey and Huneycutt 2002). Consistently, Mps1p phosphorylates a kinetochore protein termed Mad1p when the SAC is activated in yeast. The overexpression of Mps1p induces hyperphosphorylation of Mad1p and leads to cell cycle arrest in mitosis with morphologically normal spindles (Hardwick et al. 1996). In budding yeast, mutation in any of the checkpoint genes, mad1-3 and bub1-3, blocks the ability of overexpressed Mps1p to arrest the cell cycle, indicating that Mps1p is involved in the Mad- and Bub-dependent SAC pathway and may lie “high up” in the cascade (Winey and Huneycutt 2002). Mps1p-dependent phosphorylation of Ndc80/HEC1 is also likely to be important for SAC activation at kinetochores (Kemmler et al. 2009).
Xenopus Mps1 is also required for the SAC and depletion of Mps1 leads to failure of the SAC in Xenopus egg extracts (reviewed in Fisk et al. 2004). Human Mps1 was subsequently shown by antibody microinjection and siRNA approaches to be required for mitotic checkpoint arrest in response to microtubule depolymerization (Fisk et al. 2003). Zebrafish Mps1 was also found to be required for SAC signaling during wound regeneration downstream of Fibroblast Growth Factor (FGF) (see Fisk et al. 2004). In fact, Xenopus Mps1, mouse Mps1, human Mps1, and Drosophila Mps1 all localize to kinetochores, probably through the noncatalytic N-terminus, implying a conserved N-terminal kinetochore function of vertebrate Mps1. Megator (Mtor), the Drosophila counterpart of the translocated promoter region of the human nuclear pore complex protein, promotes the recruitment of Drosophila Mps1 to unattached kinetochores and mediates normal mitotic duration and the SAC response (Lince-Faria et al. 2009). In Xenopus extracts, Mps1 is required for the recruitment of CENP-E, Mad1, and Mad2 to kinetochores. In human cells, the Hec1-Ndc80-Nuf2 complex is essential for the recruitment of human Mps1 to kinetochores (Fisk et al. 2004), as is the human PRP4 kinase, whose ablation by RNAi overrides the SAC (Montembault et al. 2007). In turn, human Mps1 is physically or catalytically required for the recruitment of the SAC components Mad1 and Mad2 (Fisk et al. 2003; Tighe et al. 2008; Xu et al. 2009).
Mps1 was shown to phosphorylate Borealin (also called cell division cycle-associated protein-8, or Cdc8) to control the kinase activity of another mitotic kinase, Aurora B, thereby helping to coordinate kinetochore attachment and correct merotelic attachment error (only one kinetochore attached to both poles) alongside SAC signaling (Jelluma et al. 2008b). However, recent studies have also shown that the kinetochore localization of Mps1 may depend on Aurora B activity, suggesting that Aurora B may indeed act upstream of Mps1 (Lan and Cleveland 2010). Mps1 also phosphorylates the kinesin-related motor protein CENP-E, which relieves its autoinhibition and is likely to contribute to M-phase chromosome congression (Espeut et al. 2008) (Fig. 3).
Like many other protein kinases that control mitotic progression, Mps1 has other functions beyond those described for centrosome duplication and the SAC. A chemical and genetic approach revealed that inactivation of Mps1p generates defects in mitotic spindle formation, sister kinetochore positioning at metaphase, and chromosome segregation during anaphase, implying a multifunctional requirement for Mps1p at the kinetochore in mitotic spindle assembly and function (Jones et al. 2005). Mutation analysis of a small subset of Mps1p phosphorylation sites on a kinetochore component, Dam1p, suggested that Mps1p and Ipl1p (Aurora B) are required for coupling kinetochores to plus ends of microtubules in budding yeast (Shimogawa et al. 2006). The analysis of Mps1p function in yeast meiosis further revealed that Mps1p is required for chromosome segregation and spore wall formation (Winey and Huneycutt 2002). Additionally, Drosophila Mps1 is required for the arrest of cell cycle progression in response to hypoxia (Pandey et al. 2007) and has an important role in meiosis in female flies by regulating processes that are crucial for ensuring the proper segregation of nonexchange chromosomes (Gilliland et al. 2005, 2007). A hypomorphic Mps1 mutation also causes aneuploidy in zebrafish embryos, indicating the disastrous consequences of defects in Mps1 function in vertebrate germ-cell meiosis (Poss et al. 2004). Notably, a more recent study has shown that Mps1 is a target of microRNA miR-133 in zebrafish, during fin regeneration downstream of the FGF receptor (Yin et al. 2008).
Depletion of human Mps1 by siRNA causes mitotic catastrophe in the absence of microtubule poisons, including a high incidence of unaligned chromosomes at metaphase, large numbers of lagging chromosomes in anaphase, and failure of cytokinesis (reviewed in Fisk et al. 2004). Recent studies also suggested that the kinase activity of human Mps1 is required for proper chromosome alignment and accurate chromosome segregation. Analysis using various chemical inhibitors showed that inhibition of Mps1 kinase activity prevents correction of syntelic attachments (both kinetochores of a mitotic chromatid pair are attached to the same pole) (reviewed in Lan and Cleveland 2010), which agree with the previous finding in Mps1-depleted cells using shRNA (Jelluma et al. 2008b; Tighe et al. 2008). Mps1 also phosphorylates the Bloom syndrome gene product BLM at Ser 144, which is important for ensuring accurate chromosome segregation, and its deregulation may contribute to cancer (Leng et al. 2006).
Interestingly, human Mps1 may also participate in regulation of the G2-M DNA structure checkpoint by directly phosphorylating CHK2 on Thr 68 (Wei et al. 2005). Studies have also shown that human Mps1 controls nuclear targeting of c-Abl tyrosine kinase by 14-3-3-coupled phosphorylation at Thr 735 of c-Abl in response to oxidative stress (Nihira et al. 2008), and that a constitutively active version of the oncogenic B-Raf protein could regulate the level of Mps1, thus influencing the spindle checkpoint, in human melanoma cells (Cui and Guadagno 2008). Mps1 might also influence p53-dependent postmitotic signaling mechanisms through phosphorylation of the tumor suppressor p53 (Huang et al. 2008).
Regulation of Mps1
In the context of yeast SPB duplication, genetic evidence indicates that Mps1p requires molecular chaperones for its function. The kinase activity of Mps1p is reduced in cdc37-mutant strains, implying that Cdc37 provides a client chaperone function that promotes Mps1p activity for SPB duplication (Winey and Huneycutt 2002). Cdc28 (CDK1) also phosphorylates Mps1p on Thr 29 to maintain Mps1p levels for regulating Spc42p phosphorylation and assembly during SPB duplication (Jaspersen et al. 2004). The regulation of vertebrate Mps1 function has been reported with respect to centrosome duplication during S phase. The kinase activity of the G1-S regulator CDK2 is believed to be required for regulating Mps1 activity. In particular, human Mps1 is phosphorylated by CDK2-cyclin E in vitro at Ser 436 and Thr 453; this observation has also been made with mouse and Xenopus Mps1 (Fisk et al. 2004; Grimison et al. 2006). Furthermore, one major function for CDK2 in centrosome duplication is to prevent the proteasome-mediated degradation of Mps1 during S phase (Fisk et al. 2004; Kasbek et al. 2007). Kasbek et al. (2007) further showed that phosphorylation at Thr 468 of Mps1 by CDK2-cyclinA regulates the accumulation of Mps1 at centrosomes. Moreover, in Xenopus, mitogen-activated protein kinase (MAPK) phosphorylates Xenopus Mps1 on Ser 844, regulating its kinetochore localization (Zhao and Chen 2006). In human somatic cells or melanoma cells, B-Raf kinase signaling promotes phosphorylation and kinetochore localization of Mps1 through the MAPK pathway (Cui and Guadagno 2008; Borysova et al. 2008).
Studies in fission and budding yeast have shown that protein phosphatase-1 gamma regulates the SAC silencing mechanism by dephosphorylation of yeast checkpoint components, including Aurora B (Vanoosthuyse and Hardwick 2009; Pinsky et al. 2009). In human cells, Mps1 enzyme autoactivation (autophosphorylation) and substrate phosphorylation increases during G2, becoming maximal during mitosis (Stucke et al. 2002; Kang et al. 2007). Notably, Mps1 phosphorylation and activity are enhanced after activation of the SAC (Stucke et al. 2002), and Mps1 occupies an upstream position in the yeast SAC signaling cascade (Fisk et al. 2004). Identifying the protein phosphatase(s) that regulate Mps1 and/or inactivate the SAC in human cells is therefore an important challenge for the future. Human Mps1 phosphorylation and catalytic activity are enhanced by experimental activation of the SAC with nocodazole (Stucke et al. 2002). However, how these mitotic phosphorylation events contribute to the regulation of Mps1 activity during mitosis is not yet clear, although autophosphorylation may contribute to activation through changes in localization and/or substrate binding, or through the positioning of catalytic residues for productive catalysis. Recombinant Mps1 produced in bacteria is active when assessed by in vitro kinase assay and shows significant autophosphorylation and substrate phosphorylation when affinity-purified or immunopurified from prokaryotic or eukaryotic sources (Mattison et al. 2007; Kang et al. 2007; Jelluma et al. 2008b; Tyler et al. 2009).
The conserved activation-segment residues, Thr 676 and Thr 686, were identified as important autophosphorylation sites for the regulation of human Mps1 activity in vitro and in vivo (Mattison et al. 2007; Kang et al. 2007; Jelluma et al. 2008a; Tyler et al. 2009) (Fig. 1), and both of these sites are near-stoichiometrically modified in vitro (Johnson et al. 2009). Numerous other sites of autophosphorylation have been identified, including putative kinetochore targeting sites in the human N terminus at Thr 12 and Ser 15 (Xu et al. 2009). Tyler et al. (2009) used a combined mass-spectrometric, mutational, and phosphospecific antibody approach to identify a series of novel Mps1 autophosphorylation sites, several of which map to regions of the catalytic domain outside the activation segment. Although the in vivo function of many of these phosphorylation events is not yet known, they are important in regulating Mps1 autophosphorylation and activity in vitro (Kang et al. 2007; Tyler et al. 2009). In addition, a phosphorylated C-terminal extension is important for localization of Xenopus Mps1 to kinetochores in M-phase extracts (Zhao and Chen 2006); this conserved serine residue (Ser 844 in Xenopus Mps1 and Ser 794 in mouse Mps1) is also stoichiometrically autophosphorylated by Mps1 in vitro (Johnson et al. 2009) and highly phosphorylated on endogenous human Mps1 during mitosis (Tyler et al. 2009).
In addition to roles in centrosome duplication and the SAC, human Mps1 mRNA and protein expression are negatively regulated by the p53 protein after DNA damage (Bhonde et al. 2006). The lack of suppression of human Mps1 by p53 may contribute to DNA damage-induced apoptosis in cells (Bhonde et al. 2006). Human Mps1 activates CHK2 by phosphorylating CHK2 at Thr 68 after DNA damage. To maintain the DNA checkpoint control, activated CHK2 in turn phosphorylates Mps1 at Thr 288 and stabilizes the kinase, thus forming a positive regulatory loop (Yeh et al. 2009).
Mps1 protein levels are cell-cycle regulated and highest in rapidly proliferating tissues (Winey and Huneycutt 2002). CDK2 prevents the proteasome-mediated degradation of Mps1 during S phase (Fisk and Winey 2001), and phosphorylation of Mps1 at Thr 468 by CDK2-cyclinA regulates the accumulation of Mps1 at centrosomes in yeast (Kasbek et al. 2007). In addition, CHK2 phosphorylates Mps1 on Thr 288 and controls stability after DNA damage (Yeh et al. 2009). Several lines of indirect evidence suggest that the phosphorylation of Mps1 at Ser 844 is important for targeting and concentrating Xenopus Mps1 and Mad1 to the kinetochore and permitting M-phase checkpoint function (Zhao and Chen 2006), although this modification is clearly not important for Xenopus (Zhao and Chen 2006) or human (Tyler et al. 2009) Mps1 catalytic activity.
In anaphase, yeast Mps1p is regulated by the anaphase-promoting complex/cyclosome APC/C-Cdc20 complex. When the SAC is activated in metaphase, Mps1p acts through the checkpoint pathway to inhibit APC/C-Cdc20 activity and increase Mps1p stability, whereas in anaphase Mps1p is destabilized by APC/C-Cdc20 for mitosis exit (Palframan et al. 2006). Mps1p and APC/C-Cdc20 mutually inhibit each other to create this double-negative feedback loop (Palframan et al. 2006). However, it is still not known how yeast Mps1p localization is regulated. In human cells, Mps1 is also targeted for degradation by the APC/C-ubiquitin-proteasome pathway during late mitosis and G1 phase. A single D-box sequence, RNSL motif, was recently identified within the N-terminal region of human Mps1, which is recognized by APC/C-Cdc20 or APC/C-Cdh1 and is conserved in most mammalian species (Cui et al. 2010) (Fig. 1). The same study demonstrated that human Mps1 is a target of the APC/C-Cdc20 and APC/C-Cdh1 ubiquitin ligases, which undergoes proteolysis during anaphase through G1 phase to allow for proper centrosome duplication and cell cycle progression.
Mps1 and Disease
As a central mitotic kinase, it is not surprising that human Mps1 mRNA is found at high levels in freshly isolated malignant tissues and cancer cell lines, including breast cancer, cervical carcinoma, choriocarcinoma, hematopoietic cells, lung cancer, melanoma, neuroblastoma, ovarian cancer, and testicular tumors (Winey and Huneycutt 2002). The first data to implicate human Mps1 in tumorigenesis came with the observation that its mRNA is overexpressed in gastric cancer tissue, as well as in colon, kidney and lung cancers and bronchogenic carcinoma (Iwase et al. 1993). However, no studies have yet examined expression of Mps1 protein in parallel. Notably, Mps1 was identified in an siRNA screen of the human kinome as a modulator of cancer cell sensitivity to the microtubule-stabilizing agent, paclitaxel (Swanton et al. 2007). Dual roles of Mps1 in chromosome alignment and the SAC might be particularly important for its ability to synergize with therapeutic concentrations of paclitaxel in transformed cells (Janssen et al. 2009). These findings also indicate that Mps1 inhibition might be useful in treating patients with paclitaxel-resistant cancer, perhaps as part of a synthetic lethal strategy (Kaelin 2005). Notably, heterozygous Mps1 mutations have recently been identified in microsatellite-unstable colorectal cancers although these Mps1 mutants did not promote SAC weakening or override mitotic arrest (Niittymaki et al. 2011). By virtue of its importance in SAC signaling and its regulation of the Aurora B signaling pathway through Borealin (Jelluma et al. 2008b; Bourhis et al. 2009), Mps1 inhibition or modulation of its degradation kinetics might represent a way to sensitize or kill rapidly dividing cells (Kops et al. 2004; Kasbek et al. 2009).
Small Molecule Mps1 Inhibitors
Before 2010, only three small molecules – cincreasin (Dorer et al. 2005), SP600125 (Schmidt et al. 2005), and 1NM-PP1 (Jones et al. 2005; Tighe et al. 2008) – had been described to inhibit cellular yeast and human Mps1, respectively. Genetic and biochemical data suggest that Mps1p is a target of cincreasin, but this compound is a weak inhibitor of Mps1p, with a relatively high half-maximal inhibitory concentration of about 700 μm in an in vitro kinase assay (Dorer et al. 2005). The cell-permeant ATP analogue inhibitor 1NM-PP1 inhibits a modified M600G/A Mps1 allele and can be used to probe Mps1 function in yeast or human cells (Jones et al. 2005; Tighe et al. 2008). The ATP-competitive JNK1 inhibitor SP600125 is also a potent inhibitor of human Mps1 function. SP600125 completely inhibits Mps1 activity at 10 μm in vivo and in vitro (Schmidt et al. 2005); in contrast, it inhibits JNK1 at a half-maximal inhibitory concentration of 40 nM and is the first-choice JNK inhibitor for cellular studies (Bennett et al. 2001). Unfortunately, SP600125 also inhibits several other kinases in vitro, so its use as a specific inhibitor of Mps1 activity is prone to validation problems (Bain et al. 2007; Tighe et al. 2008). Nevertheless, SP600125 has also emerged as a potentially useful screening tool for the discovery of ATP-dependent Mps1 inhibitors through the development of fluorescent Mps1 ligand-displacement assays (Chu et al. 2010).
In 2010, six groups reported seven distinct small-molecule inhibitors of Mps1 (reviewed in Lan and Cleveland 2010; Colombo et al. 2010). Using these different chemical inhibitors, these studies demonstrated that Mps1 kinase activity is indispensable for accurate chromosome segregation through its recruitment of SAC proteins to kinetochores, formation of the APC/C-Cdc20 inhibitory mitotic checkpoint complex, and correction of erroneous microtubule attachments. However, contradictory results were described among the studies: two papers proposed that Mps1 acts upstream of Aurora B to correct syntelic attachments, while three other papers found that the kinetochore localization of Mps1 depends on Aurora B activity, suggesting that Aurora B acts upstream of Mps1 (reviewed by Lan and Cleveland 2010). An ultimate goal of Mps1 inhibitor discovery is the design of novel therapeutic agents for proliferative disorders such as cancer. Initial studies have shown that the purine analogues, 23-dMB-PP1, Mps1-IN-1, and Mps1-IN-2, all kill cultured tumor cells by direct targeting of Mps1. Colombo et al. (2010) have also described a selective, orally bioavailable, Mps1 inhibitor (NMS-P715) that reduces cancer cell proliferation and inhibits tumor growth in a preclinical model.
Crystal Structures of Human Mps1 Catalytic Domain: Insights into Mps1 Structural Biology
Most recently, Kwiatkowski et al. (2010) and Colombo et al. (2010) also reported Mps1 co-crystal structures with the kinase inhibitors, Mps1-IN-1 (2.74 Å), Mps1-IN-2 (2.6 Å), and NMS-P715 (3.1 Å), which give new insights for the design of Mps1-specific inhibitors. Significant structural difference is also found in the Mps1-IN-2 Mps1 complex. While the activation segments are absent in all other Mps1 crystal structures, it becomes ordered in the presence of this compound. Indeed, three phosphorylation sites can be observed, including Thr 675, Thr 676, and Ser 677, although the overall conformation of the catalytic domain is similar to those reported for unphosphorylated Mps1 structures (r.m.s.d. = 0.6 Å, Fig. 4c). This questions the function of the phosphorylation of these residues for Mps1 activation and the potential stabilization of a dimeric transphosphorylation complex.
Mps1 is a conserved eukaryotic dual-specificity protein kinase with an important role in centrosome duplication, SAC, chromosome alignment, and other critical cell cycle processes. Mps1 phosphorylates a growing family of cell cycle-modified proteins, and its own signaling function is controlled by phosphorylation, ubiquitination, and transient subcellular targetting. Inhibition of Mps1 activity by small molecules, either alone or as part of a multitherapy regime, might represent a novel therapeutic strategy for proliferative diseases such as cancer, where its central role as a cell cycle orchestrator makes it necessary for cell survival.
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