Mps1 Phosphorylates Borealin to Control Aurora B Activity and Chromosome Alignment

Jelluma, Nannette; Brenkman, Arjan B.; Broek, Niels J. F. van den; Cruijsen, Carin W.A.; Osch, Maria H.J. van; Lens, Susanne M.A.; Medema, René H.; Kops, Geert J. P. L.

doi:10.1016/j.cell.2007.11.046

Cited by 270 publications

(400 citation statements)

References 60 publications

Supporting

Mentioning

346

Contrasting

Unclassified

Order By: Relevance

“…Here, we characterize Nbl1 as an S. pombe Borealin-like protein based on its association with known CPC components, its colocalization with other CPC subunits during mitosis, and its sequence and proposed structural similarity to human Borealin. Consistent with previous data directly linking Borealin to Aurora B activation (Jelluma et al, 2008), we additionally demonstrate that Nbl1 is required for Ark1 activity. Furthermore, we show that the S. pombe CPC influences the process of cytokinesis, at least partially by controlling the localization of the fission yeast Cdc14-family phosphatase, Clp1.…”

Section: Discussionsupporting

confidence: 80%

A Link between Aurora Kinase and Clp1/Cdc14 Regulation Uncovered by the Identification of a Fission Yeast Borealin-Like Protein

Bohnert

Chen

Clifford

et al. 2009

MBoC

View full text Add to dashboard Cite

The chromosomal passenger complex (CPC) regulates various events in cell division. This complex is composed of a catalytic subunit, Aurora B kinase, and three nonenzymatic subunits, INCENP, Survivin, and Borealin. Together, these four subunits interdependently regulate CPC function, and they are highly conserved among eukaryotes. However, a Borealin homologue has never been characterized in the fission yeast, Schizosaccharomyces pombe. Here, we isolate a previously uncharacterized S. pombe protein through association with the Cdc14 phosphatase homologue, Clp1/Flp1, and identify it as a Borealin-like member of the CPC. Nbl1 (novel Borealin-like 1) physically associates with known CPC components, affects the kinase activity and stability of the S. pombe Aurora B homologue, Ark1, colocalizes with known CPC subunits during mitosis, and shows sequence similarity to human Borealin. Further analysis of the Clp1-Nbl1 interaction indicates that Clp1 requires CPC activity for proper accumulation at the contractile ring (CR). Consistent with this, we describe negative genetic interactions between mutant alleles of CPC and CR components. Thus, this study characterizes a fission yeast Borealin homologue and reveals a previously unrecognized connection between the CPC and the process of cytokinesis in S. pombe. INTRODUCTIONTo ensure successful cell division, sister chromatids must segregate to opposite poles of dividing cells in mitosis and be partitioned into two new daughter cells during cytokinesis (Pines and Rieder, 2001). Highly intricate mechanisms control these processes, with various macromolecular complexes coordinating their activities such that the integrity of cell division is maintained. The chromosomal passenger complex (CPC), which is composed of a catalytic subunit, Aurora B kinase, and three nonenzymatic subunits, INCENP, Survivin, and Borealin, functions as one of these critical regulatory complexes. As its name implies, this complex travels on chromosomes to various sites during cell division such that it can execute specific tasks at distinct locations and times (Earnshaw and Bernat, 1991). These functions include, but are not limited to, chromosome condensation, stabilization of the mitotic spindle, correction of improper kinetochore-microtubule attachments, and regulation of cytokinesis (for reviews, see Vagnarelli and Earnshaw, 2004;Vader et al., 2006;Ruchaud et al., 2007).The four CPC subunits are highly interdependent for proper localization, activity, and stability (Ruchaud et al., 2007). Consistent with such interdependency, these subunits are widely conserved among eukaryotes (Ruchaud et al., 2007). However, it has proven difficult to identify Borealin homologues in yeasts. Though some have speculated that yeast Borealin homologues might not exist because of fusion of the Borealin and Survivin subunits into a single yeast Survivin homologue (Vader et al., 2006), recent evidence suggests that there are in fact yeast Borealin homologues (Nakajima et al., 2009). Nonetheless, a Borealin homologue in th...

show abstract

Section: Discussionsupporting

confidence: 80%

A Link between Aurora Kinase and Clp1/Cdc14 Regulation Uncovered by the Identification of a Fission Yeast Borealin-Like Protein

Bohnert

Chen

Clifford

et al. 2009

MBoC

View full text Add to dashboard Cite

show abstract

“…The relatively small time window in which Mps1 operates likely explains why the effect of Mps1 on Aurora B centromere localization was not previously detected [10,15].…”

Section: Mps1 Allows Rapid Aurora B Recruitment To Centromeresmentioning

confidence: 96%

Mps1 promotes rapid centromere accumulation of Aurora B

et al. 2012

View full text Add to dashboard Cite

Aurora B localization to mitotic centromeres, which is required for proper chromosome alignment during mitosis, relies on Haspin‐dependent histone H3 phosphorylation and on Bub1‐dependent histone H2A phosphorylation—which interacts with Borealin through a Shugoshin (Sgo) intermediate. We demonstrate that Mps1 stimulates the latter recruitment axis. Mps1 activity enhances H2A‐T120ph and is critical for Sgo1 recruitment to centromeres, thereby promoting Aurora B centromere recruitment in early mitosis. Importantly, chromosome biorientation defects caused by Mps1 inhibition are improved by restoring Aurora B centromere recruitment. As Mps1 kinetochore localization reciprocally depends on Aurora B, we propose that this Aurora B‐Mps1 recruitment circuitry cooperates with the Aurora B‐Haspin feedback loop to ensure rapid centromere accumulation of Aurora B at the onset of mitosis.

show abstract

“…6 Although the precise contribution of MPS1 to SAC functions remains elusive, 7 accumulating evidence suggests that MPS1 facilitates SAC activation by promoting the recruitment of SAC components to unoccupied KTs. [8][9][10][11][12][13][14][15] MPS1 has also been implicated in the so-called 'error correction mechanism', 16 a poorly characterized process that resolves the erroneous KT-MT attachments that frequently form in the early steps of mitosis. 17,18 According to current models, AURKB, one component of the chromosomal passenger complex (reviewed by Ruchaud et al 19 ), catalyzes this process by destabilizing incorrect attachments, hence generating free KTs that activate the SAC.…”

mentioning

confidence: 99%

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

et al. 2013

View full text Add to dashboard Cite

,5,6,11,12,13 Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2- [(2-cyanophenyl) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals. Mitosis is a sophisticated process that ensures the faithful inheritance of the genetic material by the cellular progeny while preventing aneuploidy and chromosomal instability (CIN), two established hallmarks of cancer. 1-3 A set of protein kinases that are collectively known as mitotic kinases, including Aurora kinases (AURKs), mitotic cyclin-dependent kinases (CDKs), Polo-like kinases and monopolar spindle 1 (MPS1), regulates and coordinates multiple aspects of chromosome segregation during mitosis. 4 MPS1 (also known as TTK) is a dual-specificity kinase (meaning that it phosphorylates both serine/threonine and tyrosine residues) with an established role in the proper alignment and orientation of chromosomes on the metaphase plate. 5 MPS1 is a core component of the spindle assembl...

show abstract

Mps1 Phosphorylates Borealin to Control Aurora B Activity and Chromosome Alignment

Cited by 270 publications

References 60 publications

A Link between Aurora Kinase and Clp1/Cdc14 Regulation Uncovered by the Identification of a Fission Yeast Borealin-Like Protein

A Link between Aurora Kinase and Clp1/Cdc14 Regulation Uncovered by the Identification of a Fission Yeast Borealin-Like Protein

Mps1 promotes rapid centromere accumulation of Aurora B

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

Contact Info

Product

Resources

About