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• W2058045448 abstract "The establishment and maintenance of proper attachment of kinetochores to microtubules are required to prevent chromosome missegregation and consequent chromosomal instability and tumorigenesis. Although MST1 (mammalian sterile 20-like kinase 1) has been implicated in many aspects of cell cycle regulation and tumor suppression [1Radu M. Chernoff J. The DeMSTification of mammalian Ste20 kinases.Curr. Biol. 2009; 19: R421-R425Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], its precise mechanism of action has remained largely unknown. We now show that MST1 promotes accurate kinetochore-microtubule attachment by modulating the kinase activity of Aurora B. HeLa cells depleted of MST1 failed to develop stable end-on kinetochore-microtubule attachment, giving rise to unaligned mitotic chromosomes. The misaligned chromosomes activated the Mad2- and BubR1-dependent spindle checkpoint response, resulting in a delay in anaphase onset. The kinase activity of Aurora B, which promotes destabilization of kinetochore-microtubule attachment [2Tanaka T.U. Rachidi N. Janke C. Pereira G. Galova M. Schiebel E. Stark M.J. Nasmyth K. Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections.Cell. 2002; 108: 317-329Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar, 3Lampson M.A. Renduchitala K. Khodjakov A. Kapoor T.M. Correcting improper chromosome-spindle attachments during cell division.Nat. Cell Biol. 2004; 6: 232-237Crossref PubMed Scopus (348) Google Scholar, 4Cimini D. Wan X. Hirel C.B. Salmon E.D. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors.Curr. Biol. 2006; 16: 1711-1718Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar], was increased in cells depleted of MST1 or NDR1, a downstream kinase of MST1. MST1 and NDR1 associated with Aurora B. Moreover, MST1 directly phosphorylated Aurora B and inhibited its kinase activity in vitro. Depletion of Aurora B restored the stability of kinetochore-microtubule attachment in cells depleted of MST1 or NDR1. MST1 is thus a key regulator of Aurora B activity that ensures mitotic chromosome congression and accurate chromosome segregation. The establishment and maintenance of proper attachment of kinetochores to microtubules are required to prevent chromosome missegregation and consequent chromosomal instability and tumorigenesis. Although MST1 (mammalian sterile 20-like kinase 1) has been implicated in many aspects of cell cycle regulation and tumor suppression [1Radu M. Chernoff J. The DeMSTification of mammalian Ste20 kinases.Curr. Biol. 2009; 19: R421-R425Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], its precise mechanism of action has remained largely unknown. We now show that MST1 promotes accurate kinetochore-microtubule attachment by modulating the kinase activity of Aurora B. HeLa cells depleted of MST1 failed to develop stable end-on kinetochore-microtubule attachment, giving rise to unaligned mitotic chromosomes. The misaligned chromosomes activated the Mad2- and BubR1-dependent spindle checkpoint response, resulting in a delay in anaphase onset. The kinase activity of Aurora B, which promotes destabilization of kinetochore-microtubule attachment [2Tanaka T.U. Rachidi N. Janke C. Pereira G. Galova M. Schiebel E. Stark M.J. Nasmyth K. Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections.Cell. 2002; 108: 317-329Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar, 3Lampson M.A. Renduchitala K. Khodjakov A. Kapoor T.M. Correcting improper chromosome-spindle attachments during cell division.Nat. Cell Biol. 2004; 6: 232-237Crossref PubMed Scopus (348) Google Scholar, 4Cimini D. Wan X. Hirel C.B. Salmon E.D. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors.Curr. Biol. 2006; 16: 1711-1718Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar], was increased in cells depleted of MST1 or NDR1, a downstream kinase of MST1. MST1 and NDR1 associated with Aurora B. Moreover, MST1 directly phosphorylated Aurora B and inhibited its kinase activity in vitro. Depletion of Aurora B restored the stability of kinetochore-microtubule attachment in cells depleted of MST1 or NDR1. MST1 is thus a key regulator of Aurora B activity that ensures mitotic chromosome congression and accurate chromosome segregation. Depletion of MST1 impairs the formation of stable kinetochore-microtubule attachment Aurora B activity is increased by depletion of MST1 or NDR1 MST1 directly phosphorylates Aurora B and thereby inhibits its hyperactivation The precise regulation of Aurora B by MST1 ensures mitotic chromosome congression The kinases MST1 and MST2 have been implicated in regulation of the cell cycle and in tumor suppression, as well as in apoptotic responses [1Radu M. Chernoff J. The DeMSTification of mammalian Ste20 kinases.Curr. Biol. 2009; 19: R421-R425Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 5Saucedo L.J. Edgar B.A. Filling out the Hippo pathway.Nat. Rev. Mol. Cell Biol. 2007; 8: 613-621Crossref PubMed Scopus (285) Google Scholar]. Studies in Drosophila have identified a tumor suppressor pathway mediated by Hippo, a homolog of MST1 and MST2 [5Saucedo L.J. Edgar B.A. Filling out the Hippo pathway.Nat. Rev. Mol. Cell Biol. 2007; 8: 613-621Crossref PubMed Scopus (285) Google Scholar]. Hippo and MST phosphorylate and activate members of the nuclear Dbf2-related (NDR) family of kinases [6Wu S. Huang J. Dong J. Pan D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts.Cell. 2003; 114: 445-456Abstract Full Text Full Text PDF PubMed Scopus (831) Google Scholar, 7Chan E.H. Nousiainen M. Chalamalasetty R.B. Schäfer A. Nigg E.A. Silljé H.H. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.Oncogene. 2005; 24: 2076-2086Crossref PubMed Scopus (436) Google Scholar, 8Emoto K. Parrish J.Z. Jan L.Y. Jan Y.N. The tumour suppressor Hippo acts with the NDR kinases in dendritic tiling and maintenance.Nature. 2006; 443: 210-213Crossref PubMed Scopus (166) Google Scholar, 9Vichalkovski A. Gresko E. Cornils H. Hergovich A. Schmitz D. Hemmings B.A. NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis.Curr. Biol. 2008; 18: 1889-1895Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar]. Phosphorylation of Mob proteins by Hippo and MST also promotes activation of the NDR family kinases Warts and LATS (large tumor suppressor), respectively, leading to inhibition of cell proliferation [10Lai Z.C. Wei X. Shimizu T. Ramos E. Rohrbaugh M. Nikolaidis N. Ho L.L. Li Y. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats.Cell. 2005; 120: 675-685Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 11Wei X. Shimizu T. Lai Z.C. Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila.EMBO J. 2007; 26: 1772-1781Crossref PubMed Scopus (156) Google Scholar, 12Praskova M. Xia F. Avruch J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation.Curr. Biol. 2008; 18: 311-321Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar]. However, the precise mechanism by which MST regulates the cell cycle machinery has remained poorly understood. To elucidate the role of MST1 in the regulation of cell division, we first examined the effects of MST1 depletion by RNA interference (RNAi) on cell cycle-related events. Immunoblot analysis of cyclin B and phosphorylated histone H3 revealed that most control cells had entered mitosis by 8 hr after release from thymidine block at the G1-S transition and subsequently progressed to mitotic exit (Figure 1A). In MST1-depleted cells, however, degradation of cyclin B was delayed, and the abundance of phosphorylated histone H3 remained increased at 14 hr, suggesting that MST1 depletion results in mitotic arrest. MST1 depletion also interfered with the timely dephosphorylation of Cdc27, again indicative of a defect in mitotic exit (Figure 1A). We next monitored mitotic progression in control or MST1-depleted HeLa cells expressing green fluorescent protein (GFP)-tagged histone H2B by time-lapse microscopy (Figure 1B). Control cells exhibited properly aligned chromosomes on the metaphase plate, with the sister chromatids beginning to move toward the spindle poles at an average of ∼40 min after nuclear envelope breakdown (NEBD) (Figures 1B and 1C). However, in MST1-depleted cells, anaphase did not begin until an average of ∼74 min after NEBD as a result of a defect in chromosome alignment at the spindle equator (Figures 1B and 1C). Whereas only 5.3% of control cells failed to manifest proper chromosome alignment, 32.5% of MST1-depleted cells failed to do so (Figures 1B and 1D). MST1-depleted cells that still contained unaligned chromosomes at >2 hr after NEBD eventually underwent apoptosis (12.5%) or division (10%) (Figures 1B and 1D). These results indicate that MST1-depleted cells failed to properly form a metaphase plate, resulting in a delay in anaphase onset. The spindle checkpoint monitors chromosome-microtubule attachment and ensures that sufficient time is available for metaphase chromosome alignment. Mad2 and BubR1 are key components of the mitotic checkpoint complex and inhibit the ability of Cdc20 to activate the anaphase-promoting complex (APC-Cdc20) that is responsible for progression into anaphase [13Musacchio A. Salmon E.D. The spindle-assembly checkpoint in space and time.Nat. Rev. Mol. Cell Biol. 2007; 8: 379-393Crossref PubMed Scopus (1727) Google Scholar]. We next examined whether MST1 depletion might prolong activation of the Mad2- and BubR1-mediated spindle checkpoint. Depletion of Mad2 or BubR1 was previously shown to accelerate the timing of mitosis and to bypass mitotic arrest induced by the spindle checkpoint [14Meraldi P. Draviam V.M. Sorger P.K. Timing and checkpoints in the regulation of mitotic progression.Dev. Cell. 2004; 7: 45-60Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar]. Consistent with these observations, Mad2 depletion resulted in complete abrogation of the mitotic arrest induced by MST1 depletion, with the resulting kinetics of mitotic progression being similar to those for cells depleted of Mad2 alone (Figure 1E). Likewise, BubR1 depletion relieved the mitotic arrest induced by MST1 depletion (Figure 1F). These findings suggest that MST1 depletion induces the Mad2- and BubR1-dependent checkpoint response, resulting in a delay in anaphase onset. This activation of the spindle checkpoint is likely triggered by the unaligned mitotic chromosomes observed in MST1-depleted cells by time-lapse imaging (Figure 1B). MST1 thus appears to be required for proper mitotic chromosome alignment and thereby contributes to timely anaphase onset. Given that MST1-depleted cells failed to align chromosomes properly at the spindle equator, we next examined microtubule binding to kinetochores, impairment of which leads to chromosome misalignment. Kinetochores, as detected by staining with CREST autoimmune serum, were attached accurately to spindle microtubules on the metaphase plate of control cells (Figure 2A). In contrast, MST1-depleted cells manifested disorganized chromosomes with defective kinetochore-microtubule attachment, consistent with the results of our time-lapse analysis. We also observed defective chromosome alignment in HeLa cells depleted of MST2 or NDR1 (see Figure S1 available online), consistent with the recent report showing that MST2-mediated activation of NDR1 is important for mitotic chromosome alignment [15Chiba S. Ikeda M. Katsunuma K. Ohashi K. Mizuno K. MST2- and Furry-mediated activation of NDR1 kinase is critical for precise alignment of mitotic chromosomes.Curr. Biol. 2009; 19: 675-681Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. Moreover, we found that misaligned chromosomes of MST1-depleted cells showed either side-on or no attachment to microtubules, whereas all kinetochores of aligned chromosomes manifested stable end-on attachment to spindle microtubules in control cells (Figure 2B). MST1 thus appears to be required for proper kinetochore-microtubule attachment. To obtain further support for this conclusion, we examined whether MST1-depleted cells contain cold-stable microtubules, given that only microtubules with end-on attachment of kinetochores are resistant to cold-induced depolymerization. Whereas kinetochore-microtubule fibers remained intact after cold treatment in control cells, most microtubules underwent depolymerization in response to such treatment in MST1-depleted cells (Figure 2C). This latter finding is consistent with the presence of kinetochores with lateral or no attachment to microtubules in MST1-depleted cells (Figure 2B). MST1-depleted cells manifested weak and transient attachment of microtubules to kinetochores even when chromosomes appeared to be aligned at the spindle equator (Figure 2C, middle). We next examined whether MST1 depletion interferes with the function of kinetochore-microtubule fibers in mitotic chromosome movement and alignment during the process of spindle reorganization from a monopolar to bipolar arrangement. Monastrol, an inhibitor of the mitotic kinesin Eg5, induces mitotic arrest with a monopolar spindle [16Mayer T.U. Kapoor T.M. Haggarty S.J. King R.W. Schreiber S.L. Mitchison T.J. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen.Science. 1999; 286: 971-974Crossref PubMed Scopus (1613) Google Scholar, 17Kapoor T.M. Mayer T.U. Coughlin M.L. Mitchison T.J. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5.J. Cell Biol. 2000; 150: 975-988Crossref PubMed Scopus (569) Google Scholar]. Removal of monastrol releases cells from the arrest and results in the arrangement of chromosomes on the metaphase plate with a bipolar spindle. Control cells subjected to such treatment exhibited normal chromosome congression and alignment on the metaphase plate (Figure 2D). The chromosomes of MST1-depleted cells, however, failed to align on the metaphase plate, indicative of a lack of functional kinetochore-microtubule attachment (Figure 2D). Together, these results suggest that MST1 is required for the stable kinetochore-microtubule attachment that underlies the formation of functional kinetochore-microtubule fibers and chromosome alignment on the metaphase plate. We next explored how MST1 contributes to the stability of kinetochore-microtubule attachment and precise chromosome alignment. We found that the kinase activity of Aurora B was increased in MST1-depleted cells, as revealed by an increased level of phosphorylation of Aurora B on Thr232 (Figure 3A), which reflects kinase activity [18Yasui Y. Urano T. Kawajiri A. Nagata K. Tatsuka M. Saya H. Furukawa K. Takahashi T. Izawa I. Inagaki M. Autophosphorylation of a newly identified site of Aurora-B is indispensable for cytokinesis.J. Biol. Chem. 2004; 279: 12997-13003Crossref PubMed Scopus (184) Google Scholar]. Indeed, the ratio of phosphorylated to total Aurora B was increased ∼1.5- to 2-fold in MST1-depleted cells compared with that in control cells at 6 to 14 hr after the release of cells from thymidine block (Figure 3B). MST1 depletion did not induce the premature activation of Aurora B (Figure 3A), however, indicating that MST1 does not affect the timely activation of Aurora B. To rule out the possibility that the increased level of phosphorylation of Aurora B on Thr232 in MST1-depleted cells results from prolongation of mitosis, we directly examined the staining intensity for phosphorylated Aurora B at similar mitotic phases. Antibodies specific for Thr232-phosphorylated Aurora B were characterized in HeLa cells treated with ZM447439, a small-molecule inhibitor of Aurora B [19Ditchfield C. Johnson V.L. Tighe A. Ellston R. Haworth C. Johnson T. Mortlock A. Keen N. Taylor S.S. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores.J. Cell Biol. 2003; 161: 267-280Crossref PubMed Scopus (1045) Google Scholar] (Figure S2A). The antibodies to phospho-Aurora B recognized both centrosomes and centromeres, but only the centromere-specific staining was lost in cells treated with ZM447439, indicating that the centrosome-specific staining was attributable to Aurora A phosphorylated on Thr288 (Figure S2A). Staining with the antibodies to phospho-Aurora B as well as with antibodies to Aurora B revealed that the intensity ratio of phosphorylated to total Aurora B was increased 1.24 (±0.08)-fold in MST1-depleted cells compared with that in control cells (Figures 3C and 3D). Moreover, this ratio was increased 1.70 (±0.13)-fold in cells depleted of both MST1 and MST2, suggesting that MST1 and MST2 restrict the kinase activity of Aurora B to the appropriate level. In addition, we found that the ratio of phosphorylated to total Aurora B was increased 1.31 (±0.09)-fold in NDR1-depleted cells (Figures 3C and 3D), implicating NDR1 in the regulation of Aurora B by MST1 and MST2. Depletion of BubR1 also induced a 1.50 (±0.15)-fold increase in this ratio (Figures 3C and 3D), consistent with previous observations [20Lampson M.A. Kapoor T.M. The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments.Nat. Cell Biol. 2005; 7: 93-98Crossref PubMed Scopus (245) Google Scholar]. We next further investigated whether the function of MST in regulating Aurora B activity is conserved in mouse embryonic fibroblasts (MEFs). Increased phosphorylation of Aurora B on Thr232 was observed in Mst1−/− MEFs, but not in Mst2−/− MEFs (Figures S2B and S2C). Although this latter finding appears to be inconsistent with the results obtained by RNAi-mediated depletion of MST1 or MST2 in HeLa cells, previous study has shown that Mst1 and Mst2 functionally compensate for each other during mouse development [21Oh S. Lee D. Kim T. Kim T.S. Oh H.J. Hwang C.Y. Kong Y.Y. Kwon K.S. Lim D.S. Crucial role for Mst1 and Mst2 kinases in early embryonic development of the mouse.Mol. Cell. Biol. 2009; 29: 6309-6320Crossref PubMed Scopus (107) Google Scholar], suggesting that Mst1 may have sufficiently compensated for Mst2 function in Mst2−/− MEFs in regulating Aurora B activity. Consistently, Mst1−/−; Mst2+/− MEFs had a higher level of phosphorylated Aurora B on Thr232 compared with that of Mst1−/−; Mst2+/+ MEFs (Figures S2B and S2D). Thus, both Mst1 and Mst2 regulate Aurora B activity, with Mst1 being a dominant regulator and Mst2 functioning when Mst1 is deficient. We next examined whether MST1 might directly regulate Aurora B activity. Immunoprecipitation analysis revealed that hemagglutinin (HA) epitope-tagged MST1 associated with Flag epitope-tagged Aurora B (Figure 3E) and that the COOH-terminal kinase domain of Aurora B was sufficient for its binding to MST1 (Figure S2E). A HA-tagged MST1 kinase-dead form whose ATP-binding site was mutated did not efficiently bind to Flag-Aurora B, suggesting that the association of MST1 with Aurora B is dependent on the kinase activity of MST1 (Figure 3E). A purified glutathione S-transferase (GST)-tagged kinase-dead mutant of Aurora B (Figure S2F) was efficiently phosphorylated by both immunoprecipitated GFP-Flag-MST1 (Figure S2G) and purified GST-MST1 (Figure 3F), but not by the kinase-dead mutant of MST1. Moreover, GST-MST1 or purified His6-tagged MST1, but not the kinase-dead mutant of MST1, inhibited the kinase activity of purified Aurora B measured with a known substrate, histone H3, in vitro (Figure 3G; Figure S2H), suggesting that MST1 inhibits the kinase activity of Aurora B through direct phosphorylation. We also found that NDR1 associated with Aurora B and that expression of MST1 with NDR1 increased the extent of Aurora B-NDR1 association (Figures S2I and S2J), suggesting that MST1-mediated activation of NDR1 promotes its binding to Aurora B. We further determined whether MST1, NDR1, and Aurora B form a tripartite complex by performing sequential immunoprecipitation analysis. Whereas Flag-Aurora B was again coprecipitated with HA-MST1, the precipitate did not contain detectable HA-NDR1 (Figure S2K), suggesting that the three proteins do not form a stable tripartite complex. However, given that MST1 activates NDR1 and promotes its association with Aurora B, we are not able to exclude the possibility that the three proteins form a transient weak complex. Together, our in vitro and in vivo results suggest that MST1 inhibits hyperactivation of Aurora B directly by phosphorylating Aurora B as well as indirectly via regulation of NDR1. Given that depletion of MST1 or NDR1 resulted in hyperactivation of Aurora B, we next examined whether an increase in the kinase activity of Aurora B might induce chromosome misalignment similar to that observed in cells depleted of MST1 or NDR1. To address this issue, we examined mitotic HeLa cells overexpressing Aurora B. We found that 55% of cells overexpressing Aurora B exhibited kinetochores that were unattached to microtubules and chromosomes that failed to align at the metaphase plate (Figures 4A and 4B). To further determine whether the defect in kinetochore-microtubule attachment in cells depleted of MST1 or NDR1 is attributable to the hyperactivation of Aurora B, we tested whether inhibition of Aurora B might rescue the phenotype induced by MST1 or NDR1 depletion. Exposure of MST1-depleted cells to ZM447439 revealed that the mitotic arrest induced by MST1 depletion was partially relieved in the presence of ZM447439 (Figure S3A). However, we could not exclude the possibility that this finding was attributable to a defective spindle checkpoint in the ZM447439-treated cells, given that ZM447439 compromises the spindle checkpoint, likely by interfering with the kinetochore localization of BubR1, Mad2, and CENP-E [19Ditchfield C. Johnson V.L. Tighe A. Ellston R. Haworth C. Johnson T. Mortlock A. Keen N. Taylor S.S. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores.J. Cell Biol. 2003; 161: 267-280Crossref PubMed Scopus (1045) Google Scholar]. We therefore examined kinetochore-microtubule attachment in cells depleted of both MST1 and Aurora B (Figure 4C; Figure S3B). Cells depleted of both MST1 and Aurora B manifested more cold-stable microtubules than did cells depleted of MST1 alone (Figure 4C), indicating that hyperactivation of Aurora B was responsible for unstable kinetochore-microtubule attachment in MST1-depleted cells. Depletion of Aurora B also conferred a stable microtubule configuration in NDR1-depleted cells subjected to cold treatment (Figure 4D; Figure S3C). Together, these results suggest that Aurora B depletion prevented the development of unstable kinetochore-microtubule attachment induced by depletion of MST1 or NDR1. In conclusion, we have provided evidence that MST1 limits the extent of Aurora B activation in order to promote stable kinetochore-microtubule attachment and chromosome alignment during mitosis (Figure 4E). In MST1-depleted cells, the lack of proper kinetochore-microtubule attachment prevented accurate chromosome alignment on the metaphase plate and thereby triggered activation of the spindle checkpoint in a manner dependent on Mad2 and BubR1, ultimately leading to a delay in the onset of anaphase. Together with the recent demonstration of the mitotic activation of MST1 and MST2 [12Praskova M. Xia F. Avruch J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation.Curr. Biol. 2008; 18: 311-321Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 15Chiba S. Ikeda M. Katsunuma K. Ohashi K. Mizuno K. MST2- and Furry-mediated activation of NDR1 kinase is critical for precise alignment of mitotic chromosomes.Curr. Biol. 2009; 19: 675-681Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar], our present results support the notion that MST1 and MST2 contribute to normal mitotic progression. Moreover, we showed that hyperactivation of Aurora B is responsible for the improper kinetochore-microtubule attachment and chromosome misalignment observed in MST1- or NDR1-depleted cells. Aurora B has been proposed to function as a key regulator of kinetochore-microtubule attachment. Active Aurora B has been shown to promote the turnover of kinetochore-microtubule fibers and to destabilize kinetochore-microtubule attachment through phosphorylation and regulation of its substrates, including HEC1 (Ndc80) and the microtubule depolymerase MCAK [2Tanaka T.U. Rachidi N. Janke C. Pereira G. Galova M. Schiebel E. Stark M.J. Nasmyth K. Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections.Cell. 2002; 108: 317-329Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar, 3Lampson M.A. Renduchitala K. Khodjakov A. Kapoor T.M. Correcting improper chromosome-spindle attachments during cell division.Nat. Cell Biol. 2004; 6: 232-237Crossref PubMed Scopus (348) Google Scholar, 4Cimini D. Wan X. Hirel C.B. Salmon E.D. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors.Curr. Biol. 2006; 16: 1711-1718Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 22DeLuca J.G. Gall W.E. Ciferri C. Cimini D. Musacchio A. Salmon E.D. Kinetochore microtubule dynamics and attachment stability are regulated by Hec1.Cell. 2006; 127: 969-982Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar, 23Andrews P.D. Ovechkina Y. Morrice N. Wagenbach M. Duncan K. Wordeman L. Swedlow J.R. Aurora B regulates MCAK at the mitotic centromere.Dev. Cell. 2004; 6: 253-268Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, 24Bakhoum S.F. Thompson S.L. Manning A.L. Compton D.A. Genome stability is ensured by temporal control of kinetochore-microtubule dynamics.Nat. Cell Biol. 2009; 11: 27-35Crossref PubMed Scopus (324) Google Scholar]. In the present study, we showed that MST1 limits the basal kinase activity of Aurora B, likely through direct phosphorylation. This study adds another aspect to regulation of Aurora B kinase activity, which is already known to be enhanced by INCENP, borealin, and survivin [25Vader G. Medema R.H. Lens S.M. The chromosomal passenger complex: Guiding Aurora-B through mitosis.J. Cell Biol. 2006; 173: 833-837Crossref PubMed Scopus (233) Google Scholar] and negatively regulated by protein phosphatases 1 and 2A [26Sugiyama K. Sugiura K. Hara T. Sugimoto K. Shima H. Honda K. Furukawa K. Yamashita S. Urano T. Aurora-B associated protein phosphatases as negative regulators of kinase activation.Oncogene. 2002; 21: 3103-3111Crossref PubMed Scopus (132) Google Scholar]. Recently, physical tension has been shown to modulate the relative spatial distributions of Aurora B and its substrates, ultimately determining the phosphorylation of its substrates [27Liu D. Vader G. Vromans M.J. Lampson M.A. Lens S.M. Sensing chromosome bi-orientation by spatial separation of aurora B kinase from kinetochore substrates.Science. 2009; 323: 1350-1353Crossref PubMed Scopus (416) Google Scholar]. The direct regulators of Aurora B kinase activity thus might affect the extent of substrate phosphorylation after repositioning of Aurora B closer to its substrates through physical tension. Therefore, the kinase activity of Aurora B is likely strictly regulated at multiple levels during mitotic progression. Indeed, expression of Aurora proteins is increased in many cancers in which dysregulated activation of these kinases might promote genomic instability [28Katayama H. Brinkley W.R. Sen S. The Aurora kinases: Role in cell transformation and tumorigenesis.Cancer Metastasis Rev. 2003; 22: 451-464Crossref PubMed Scopus (376) Google Scholar]. The expression of MST1 was found to be downregulated in human soft tissue sarcoma [29Seidel C. Schagdarsurengin U. Blümke K. Würl P. Pfeifer G.P. Hauptmann S. Taubert H. Dammann R. Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma.Mol. Carcinog. 2007; 46: 865-871Crossref PubMed Scopus (133) Google Scholar] and human colorectal cancer [30Minoo P. Zlobec I. Baker K. Tornillo L. Terracciano L. Jass J.R. Lugli A. Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer.Mod. Pathol. 2007; 20: 331-338Crossref PubMed Scopus (62) Google Scholar]. Our results thus support the emerging role of MST1 in tumor suppression by showing that MST1 negatively regulates Aurora B activity and thereby contributes to the fidelity of chromosome segregation." @default.
• W2058045448 created "2016-06-24" @default.
• W2058045448 creator A5013328806 @default.
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• W2058045448 date "2010-03-01" @default.
• W2058045448 modified "2023-10-18" @default.
• W2058045448 title "MST1 Limits the Kinase Activity of Aurora B to Promote Stable Kinetochore-Microtubule Attachment" @default.
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