SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2109322693> ?p ?o ?g. }

Showing items 1 to 100 of ±160 with 100 items per page.

W2109322693 endingPage "2173" @default.
W2109322693 startingPage "2162" @default.
W2109322693 abstract "Focus Review23 July 2009free access A quantitative systems view of the spindle assembly checkpoint Andrea Ciliberto Corresponding Author Andrea Ciliberto IFOM—Firc Institute of Molecular Oncology, Milan, Italy Search for more papers by this author Jagesh V Shah Corresponding Author Jagesh V Shah Department of Systems Biology, Harvard Medical School and Renal Division, Brigham and Women's Hospital, Boston, MA, USA Search for more papers by this author Andrea Ciliberto Corresponding Author Andrea Ciliberto IFOM—Firc Institute of Molecular Oncology, Milan, Italy Search for more papers by this author Jagesh V Shah Corresponding Author Jagesh V Shah Department of Systems Biology, Harvard Medical School and Renal Division, Brigham and Women's Hospital, Boston, MA, USA Search for more papers by this author Author Information Andrea Ciliberto 1 and Jagesh V Shah 2 1IFOM—Firc Institute of Molecular Oncology, Milan, Italy 2Department of Systems Biology, Harvard Medical School and Renal Division, Brigham and Women's Hospital, Boston, MA, USA *Corresponding authors: IFOM—Firc Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy. Tel.: +390 257 430 3253; Fax: +390 257 430 3231; E-mail: [email protected] of Systems Biology, Harvard Medical School and Renal Division, Brigham and Women's Hospital, 4 Blackfan Circle, Boston, MA 02115, USA. Tel.: +1 617 525 5912; Fax: +1 617 525 5965; E-mail: [email protected] The EMBO Journal (2009)28:2162-2173https://doi.org/10.1038/emboj.2009.186 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info The idle assembly checkpoint acts to delay chromosome segregation until all duplicated sister chromatids are captured by the mitotic spindle. This pathway ensures that each daughter cell receives a complete copy of the genome. The high fidelity and robustness of this process have made it a subject of intense study in both the experimental and computational realms. A significant number of checkpoint proteins have been identified but how they orchestrate the communication between local spindle attachment and global cytoplasmic signalling to delay segregation is not yet understood. Here, we propose a systems view of the spindle assembly checkpoint to focus attention on the key regulators of the dynamics of this pathway. These regulators in turn have been the subject of detailed cellular measurements and computational modelling to connect molecular function to the dynamics of spindle assembly checkpoint signalling. A review of these efforts reveals the insights provided by such approaches and underscores the need for further interdisciplinary studies to reveal in full the quantitative underpinnings of this cellular control pathway. Introduction The goal of mitosis is to take the duplicated genome, in the form of chromosomes, and ensure its equal distribution to each daughter cell. This distribution is carried out by the mitotic spindle, a complex machine that captures the duplicated chromosomes at their centromeres and segregates them. The fidelity and control of this process is governed by the spindle assembly checkpoint, a cellular pathway that delays chromosome segregation, or anaphase, until they have all been appropriately captured by the mitotic spindle. Failure of the spindle assembly checkpoint results in gain and loss of chromosomes, or aneuploidy, a condition associated with malignancy and birth defects. Given its role, it is not surprising, but yet striking, that the spindle assembly checkpoint can delay anaphase in response to a single uncaptured chromosome, exhibiting excellent sensitivity. Once this last chromosome attaches, the spindle assembly checkpoint disengages and rapidly promotes anaphase onset. High fidelity and speed are usually competing design constraints in man-made machines, and as such the underlying logic and quantitative mechanisms of the spindle assembly checkpoint are of interest to life scientists and physical scientists alike. Here, we present a systems view of the spindle assembly checkpoint in which we modularize the complexity of the components into the key communicating elements and consider the measurements and modelling of these elements that have started to reveal the quantitative basis of this exquisite cellular control mechanism. Spindle assembly checkpoint signalling—a primer The basic schema of the spindle assembly checkpoint is a balance between an inhibitory signal to prevent anaphase and the activity of the anaphase-promoting machinery (Figure 1). The key site in the production of the inhibitory signal is the kinetochore, a protein complex that assembles at the centromere of mitotic chromosomes (reviewed in an accompanying contribution from Santaguida and Musacchio). The unattached kinetochore acts as a catalytic scaffold for inhibitor production. As cells enter mitosis, all kinetochores are unattached and generate a signal that acts to prevent the onset of anaphase through direct inhibition of the anaphase promoting machinery (Figure 1A). The capture of chromosomes at both sister kinetochores, by microtubules of the mitotic spindle, silences the production of this signal (Figure 1B and C). The stoppage in inhibitor production leads to the activation of anaphase-promoting activity. The origin of the anaphase-promoting activity is an E3 ubiquitin ligase, aptly named the anaphase-promoting complex or APC/C (King et al, 1995; Sudakin et al, 1995). To promote anaphase onset the APC/C, activated by its cofactor Cdc20, ubiquitinates (Fang et al, 1998a), and thereby targets for destruction by the proteasome, cyclin B and securin (Glotzer et al, 1991). Loss of cyclin B begins the program of mitotic exit through the reduction of cyclin-dependent kinase (Cdk1) activity. Loss of securin releases the activity of a protease known as separase that cleaves the ‘molecular glue’, or cohesin complexes, which bind replicated chromatids together (Figure 1D). This transition to anaphase promotes both the segregation of the genetic material, and exit into the subsequent cell cycle for both progeny cells. The spindle assembly checkpoint delays APC/C activation until all kinetochores are properly attached to microtubules. Figure 1.Schematic view of spindle assembly checkpoint signalling. (A) Cells enter mitosis with unattached kinetochores that actively generate inhibitory signals (strong red alarm signal) to prevent APC/C activation. This stabilizes the high levels of cyclin B and securin that prevent anaphase onset. (B) Attachment of spindle microtubules to unattached kinetochores locally turns off kinetochore-mediated inhibition, but cytoplasmic inhibition, potentially diminished, is still supported by other unattached kinetochores (weaker red signal). The progressive attachment of microtubules generates a weak signal in the cytoplasm that promotes the disengagement of the checkpoint (weak green alarm signal) (C) Capture of all chromosomes results in the complete loss of signal generation from kinetochores (weakest red signal), permitting the greater relief of inhibition on the APC/C in the cytoplasm (stronger green alarm). Activation of the APC/C promotes the destabilization of cyclin B and securin. (D) Sufficient loss of substrates (cyclin B and securin) promotes the activation of separase and cleavage of the cohesins permitting the onset of anaphase and segregation of the sister chromatids. Download figure Download PowerPoint The generation of the inhibitory signal and its mode of inhibition have been widely studied (reviewed in Musacchio and Salmon, 2007). Less well understood are the mechanisms for relieving the inhibition of the APC/C and permitting the transition to anaphase. Together, these activities, inhibition on the one hand and release of that inhibition on the other, must support the widespread observation of a single unattached kinetochore delaying the onset of anaphase. Moreover, the coupling of these activities and their relative dominance must be controlled entirely through kinetochore attachment to permit the rapid transition to anaphase on kinetochore attachment. Each of these activities: inhibitor generation, release from inhibition and kinetochore attachment are themselves complex signalling pathways involving a myriad of molecular components. A systems view of spindle assembly checkpoint signalling focuses our attention onto the communication between signalling modules that are likely to govern the quantitative dynamics of this pathway. A modular view of spindle assembly checkpoint signalling The spindle assembly checkpoint requires the coordination between many signalling pathways. Unattached kinetochores produce a signal that informs the cytoplasm of the lack of chromosome attachment. Once engaged, the attachment machinery promotes the silencing of the kinetochore-based signalling platform. Finally, the fulfillment of a state of kinetochore attachment for all chromosomes must be transmitted, either actively or passively to the cytoplasm to activate the anaphase-promoting machinery. From this simple description we can identify three major modules: the kinetochore-localized signalling platform, the spindle attachment machinery and the cytoplasmic activities associated with APC/C activity (Figure 2A). The modules act to abstract internal molecular interactions, some of which are still unknown, in favour of those inter-module interactions that regulate rapid information transfer and are likely to support the observed dynamics. Figure 2.Modular organization of the spindle assembly checkpoint. (A) The interactions between the modules that comprise the spindle assembly checkpoint. The K-microtubule module represents the proteins at the kinetochore that control microtubule attachment. The K-checkpoint module, the network of proteins at the kinetochores that generate the inhibitory flux of Mad2:Cdc20 and A*. Finally, the cytoplasm module represents the reactions of MCC:APC/C association and release taking place in the cytoplasm—the balance between APC/C inhibition and its release. The filled arrows represent the molecular interactions controlling the activity of the scaffold at the unattached kinetochore. The open arrows indicate net fluxes, which result in the generation of Mad2:Cdc20 complexes from the unattached kinetochores and the release of free Cdc20 through active dissociation within the cytoplasm. (B) The spindle assembly checkpoint signalling elements of the kinetochore (K-Checkpoint) catalyse, through the Mad1:Mad2 scaffold, the formation of Mad2:Cdc20 complexes. In this representation, the kinetochore can also modulate the level of cytoplasmic MCC:APC/C dissociation activity through the proposed A to A* modification. Red complexes act to inhibit APC/C activity, whereas green activate. (C) The microtubule attachment module of the kinetochore (K-Microtubule) involves the microtubule attachment complex, Ndc80, and the Dynein-binding protein Spindly. The action of Spindly and the Rod–Zw10–Zwilch complex (RZZ) controls indirectly, through microtubule attachment, kinetochore-mediated inhibitor generation. (D) The cytoplasm has three submodules. The first forms the MCC:APC/C inhibitory complex from the Mad2:Cdc20 complex and other cytoplasmic components (BubR1:Bub3 and APC/C). The second actively dissociates the inhibited APC/C into the component parts, through the activity of A. Note that A* (inactive) is converted to A (active) in the cytoplasmic module. The third component comprises non-kinetochore mechanisms for generation of the Mad2:Cdc20 complex, specifically through cytoplasmic amplification from Closed Mad2 complexes in the cytoplasm (Mad2:Cdc20, MCC (not shown) and MCC:APC/C). This last reaction is represented with a dashed line. Download figure Download PowerPoint Kinetochore-mediated signal generation The assembly of the kinetochore is a complex process that involves a host of proteins (see this issue Santaguida and Musacchio and Musacchio and Salmon, 2007). The checkpoint elements of the kinetochore were originally revealed in a set of seminal budding yeast screens that gave rise to the mitotic arrest deficient (Mad 1, 2 and 3) and budding inhibited by benzimidazole (Bub1 and 3) genes that sparked the molecular understanding of the checkpoint (Hoyt et al, 1991; Li and Murray, 1991). Central to these gene products is their specific localization or enrichment at unattached kinetochores, as first revealed by Chen and Murray and Li and Benezra for the vertebrate orthologue of Mad2 (Chen et al, 1996; Li and Benezra, 1996). The inhibitor generation signalling paradigm of the kinetochore was first demonstrated by Rieder and colleagues who through the laser-mediated ablation of the last unattached kinetochore and the resulting precocious onset of anaphase identified the kinetochore as the source of the anaphase inhibitory signal (Rieder et al, 1995). Finally, the observation of Mad2 turnover at unattached kinetochores (Howell et al, 2000) solidified the widely held model of checkpoint signalling by which the unattached state of the kinetochore is transmitted to the cytoplasm through the transient recruitment and activation of Mad2 (Figure 2B). By the time of the demonstration of kinetochore turnover, Mad2 had already been shown to interact with Cdc20, the activator of the mitotic APC/C, and to inhibit APC/C activity (He et al, 1997; Li et al, 1997; Hwang et al, 1998; Kallio et al, 1998; Kim et al, 1998; Wassmann and Benezra, 1998; Fang et al, 1998b). Moreover, in seminal work by Sudakin et al (2001), a potent inhibitory complex, the mitotic checkpoint complex (MCC), was found to contain Mad2, Cdc20, BubR1/Mad3 and Bub3 proteins, all found enriched at unattached kinetochores. Further studies revealed that all components of the MCC turnover at unattached kinetochores (Howell et al, 2000, 2004; Kallio et al, 2002; Shah et al, 2004) further supporting the role of the unattached kinetochore as the catalytic platform for inhibitor production. Detailed structural studies demonstrated that the first step in the formation of this inhibitor occurs through the conformational activation of Mad2 (Xia et al, 2004; De Antoni et al, 2005; Yang et al, 2008). Structural studies of the Mad2 conformational change, pioneered by the laboratories of Yu and Musacchio, showed that the Mad1-bound form of Mad2 (Closed or N2), can induce a second Mad2 molecule, normally in the Open or N1 conformation in the cytoplasm, to acquire the active conformation (Closed or N2). Thus activation requires a transient dimerization (Mapelli et al, 2007; Yang et al, 2008) that occurs at the unattached kinetochore, in which Mad2 is in the closed form bound to Mad1 (Mapelli et al, 2006). This transient dimerization was observed in living cells by Shah and colleagues who demonstrated that only a proportion (∼50%) turned over at kinetochores and that the remainder was stable, presumably bound to stable Mad1 (Shah et al, 2004). Activation permits Mad2 to bind Cdc20 resulting in a Mad2:Cdc20 complex incapable of activating the APC/C. The complete MCC also includes the checkpoint proteins BubR1 (Mad3 in lower organisms) and Bub3 that bind the Mad2:Cdc20 complex at the kinetochore or in the cytoplasm and it is this complex that acts to inhibit APC/C activity (Millband and Hardwick, 2002; Davenport et al, 2006; Essex et al, 2009; Kulukian et al, 2009). It is important to note that a number of other proteins (Mps1, Bub1, Aurora B, Plk1, CENP-E, CENP-F, etc.), and in particular kinases, have been shown to have a function in the checkpoint. In some cases, these proteins may be required for assembly of the catalytic platform itself. However, it is also possible that these proteins have a more direct function in APC/C inhibition, or its relief. For example, the checkpoint kinase Bub1, has a key function in recruitment of checkpoint proteins to kinetochores (Meraldi and Sorger, 2005) but also can phosphorylate Cdc20 to prevent it from interacting with APC/C or spindle assembly checkpoint components potentially acting to buffer Cdc20 levels during spindle assembly checkpoint activation (Tang et al, 2004). Such distinct activities in spindle checkpoint signalling can also be proposed for Mps1, Aurora B and Plk1 kinases. As such, in our representation of the modules comprising the spindle assembly checkpoint, protein activities (like those described for Bub1) can be split between the assembly of the catalytic scaffold (Figure 2B) and ‘A’, an abstract quantity whose activity directly regulates APC/C inhibition (Figure 2B and D) through an alternative pathway, depicted here as a regulator of MCC:APC/C dissociation. At its core, this module takes as input Cdc20 and Mad2 and a hypothetical activity ‘A’, that acts to release APC/C inhibition, and produces an inhibitory Mad2:Cdc20 complex and ‘A*’, an inactive form of A. Both outputs act to inhibit APC/C activity and thus prevent anaphase onset. The quantitative production rates of these species are the central quantities of interest that emerge from this module and must ultimately account for single kinetochore inhibition. Microtubule-binding interface and kinetochore-localized signal silencing machinery In addition to the generation of the checkpoint signal, the kinetochore also acts to capture and stabilize spindle microtubules, ultimately using them to power transport of sister chromatids to the presumptive daughter cells. The molecular components involved in this process are numerous, but restricting our focus to the spindle checkpoint permits the definition of an interface between the microtubule-binding components and spindle checkpoint components of the kinetochore. Importantly, these components at the interface are candidates to regulate the activity of the catalytic scaffold permitting the silencing of the signal generation on microtubule attachment. Key candidates for this interface are the Ndc80 and the Rod–Zw10–Zwilch (RZZ) complexes (Figure 2C). The Ndc80 complex is a major microtubule-binding component of the kinetochore and is widely conserved in evolution. Reduction of Ndc80 complex levels (through the modulation of the Hec1 subunit) results in the dramatic loss of stable spindle attachments (Cheeseman et al, 2006; DeLuca et al, 2006) but also diminishes Mad2 (Martin-Lluesma et al, 2002; Guimaraes et al, 2008) and RZZ complex recruitment to kinetochores (Lin et al, 2006; Miller et al, 2008). Surprisingly, the checkpoint remains active under this reduction of recruited Mad2, and Mad2 is recruited to normal levels if cells are subjected to spindle poisons (Guimaraes et al, 2008). As expected, complete loss of the Ndc80 complex results in the complete absence of a mitotic checkpoint underscoring the minimal requirement for Mad2 recruitment to establish and maintain a checkpoint arrest (Meraldi et al, 2004). In addition to Ndc80, Mad2 localization and kinetochore-mediated checkpoint activation is dependent on the RZZ complex (Kops et al, 2005; Griffis et al, 2007). This complex, which is present only in metazoans, is recruited to kinetochores to establish a docking site for the molecular motor Dynein (Starr et al, 1998) mediated through the recently identified protein Spindly/SPDL-1 (Griffis et al, 2007; Gassmann et al, 2008; Yamamoto et al, 2008). Once Dynein is engaged at the kinetochore, it interacts with spindle microtubules. Notably, when the microtubule interaction is stabilized, the kinetochore, or more precisely the Mad2 recruitment portion of the catalytic scaffold, is carried away by the Dynein–RZZ complex along the captured spindle microtubules to the spindle poles. This mechanism is critical as it provides a local mechanism for signal silencing that otherwise maintains active checkpoint signalling in the presence of attached kinetochores (Howell et al, 2001; Buffin et al, 2005; Sivaram et al, 2009). Given this role in streaming Mad2, and a portion of the catalytic scaffold, away from attached kinetochores, it is not surprising that the RZZ complex is also required for the localization of Mad2 and an intact checkpoint. Together, RZZ and the Ndc80 complexes regulate both microtubule attachments and the recruitment of Mad2. Recent work from Gassmann and colleagues has provided a critical link between RZZ and Ndc80 that depends on the Spindly protein (Gassmann et al, 2008). Through mediation of the maturation of the microtubule attachment, Spindly is proposed to determine the handoff of the microtubule from RZZ–Dynein to the Ndc80 complex and is thus poised to simultaneously regulate microtubule attachments and the inhibitor generation activity at the kinetochore (Civril and Musacchio, 2008) (Figure 2C). This emerging picture provides a key connection between microtubule attachment and the local inactivation of inhibitor generation at the kinetochore. Cytoplasmic activities of APC/C activity and regulation Although the kinetochore has been of tremendous interest in checkpoint dynamics, a significant portion of checkpoint activity also takes place through cytoplasmic interactions that remain poorly understood. The cytoplasmic ‘module’, as such, has many potential interactions with the kinetochore reflecting a complex communication with the unattached kinetochore that are likely to go beyond the reliance on a single diffusible stoichiometric inhibitor. As described above, the kinetochore can provide a scaffold for the generation of the Mad2:Cdc20 complex that can become a full MCC complex either at the kinetochore (Howell et al, 2004; Shah et al, 2004) or in the cytoplasm (Essex et al, 2009; Kulukian et al, 2009) by binding the BubR1:Bub3 complex (Figure 2D). As the APC/C is not specifically localized within cells, although it is enriched on the spindle, at spindle poles (Huang and Raff, 2002) and centromeres (Acquaviva et al, 2004), it is widely held that the diffusion of this complex from the kinetochore into the cytoplasm is critical for forming the inhibitory MCC:APC/C complex (Sudakin et al, 2001; Herzog et al, 2009). Once bound to the APC/C, the MCC acts as a pseudosubstrate inhibitor with BubR1/Mad3 having a key function in inhibiting the recruitment of anaphase targets to the APC/C that would otherwise be recruited by Cdc20 (Burton and Solomon, 2007). Once formed, the spontaneous dissociation rate of the MCC:APC/C complex is small as observed in vitro and in mitotic extracts, indicating a tight interaction (Reddy et al, 2007). However, the presumed rate of dissociation, indirectly observed in vivo after all kinetochores having attached, is relatively rapid (Clute and Pines, 1999; Morrow et al, 2005; Braunstein et al, 2007; JVS unpublished data). The dissociation of the MCC from the APC/C, and the deactivation of Mad2, has been proposed by Reddy and colleagues to occur through Cdc20 ubiquitination in the context of the MCC:APC/C in complex with its E2 enzyme UbcH10 (Reddy et al, 2007). This process may itself be balanced by deubiquitination by the deubiquitinating enzyme USP44 (Stegmeier et al, 2007). The Cdc20 modification is a non-degradative ubiquitination, which is proposed to break the complex formed between Mad2 and Cdc20, a role played by the generic molecule ‘A’ (Figure 2D). Given that the binding of Cdc20 and Mad2 is expected to be a spontaneous process in living cells, this piece of data provides a potential source of energy needed to destabilize the complex (Simonetta et al, 2009). It is tempting to integrate these observations into a model of the checkpoint whereby unattached kinetochores not only control the formation of the inhibitor but also its dissociation, as is proposed by the modulation of A by the kinetochore catalytic scaffold. It can be argued that with this wiring, the spindle assembly checkpoint would guarantee a more effective inhibition and faster release of Cdc20 as compared with a system in which signalling only controls the formation of the inhibitor (see Box 1 for a more detailed description). Box 1 Dynamical regulation of inhibitor generation abd dissolution: Faucets, Sinks and Plugs Box 1 It is well known and accepted that the spindle assembly checkpoint helps the formation of Mad2:Cdc20, and subsequent MCC:APC/C complexes through the activity of Mad1:Mad2. Recent evidence suggests that the checkpoint could also act through stabilizing the MCC:APC/C complex. Reddy, Stegmeier, Rape and collaborators showed that the MCC:APC/C complex can be dissociated by ubiquitination (Reddy et al, 2007), a reaction opposed by the deubiquitinase USP44 (Stegmeier et al, 2007), whose activity has been found high in mitotic extract. It is not known whether the checkpoint indeed activates USP44 (a potential mechanism for A to A* conversion in Figure 1). It is, however, interesting to investigate the dynamical consequences of a system in which the checkpoint only induces the formation of MCC:APC/C as compared with a system in which it both induces its formation and stabilizes it. The two can be described metaphorically by a sink, in which MCC:APC/C is represented by the water accumulated in the basin. If the spindle checkpoint acts simply by favouring the production of MCC:APC/C—panel A, opening of the faucet—we have to assume that the spontaneous dissociation of MCC:APC/C must be small compared with the influx of MCC:APC/C for the checkpoint to efficiently inhibit APC/C (thin pipe). As a consequence, the silencing of the checkpoint will necessarily be dictated by the slow rate of disappearance of MCC:APC/C resulting in a long delay between the switching off the kinetochore (faucet is closed) and spindle assembly checkpoint silencing (basin empty). If, on the other hand, the spindle assembly checkpoint not only contributes with ‘faucet’ molecules (MCC:APC/C), but also with ‘plug’ molecules that stabilize MCC:APC/C—panel B—the dynamics can be quite different. Here, we can imagine that a fast rate of MCC:APC/C dissociation (wide pipe) is masked by the activity of the checkpoint (plug in wide pipe). As soon as the kinetochores are attached, not only does the influx of MCC:APC/C cease (faucet is closed) but the inhibition is relieved as well (plug is removed) and Cdc20 can be re-activated (basin empty) with a much faster pace. Here, we discuss this activity through the species ‘A’ that has yet to be verified or provided with a molecular correlate. However, the emerging modelling and molecular data suggest that such a pathway is likely to be present. The proposed dissociation pathway has been brought into question by recent data suggesting that Cdc20 ubiquitination is not required for checkpoint exit but instead to keep the level of Cdc20 low during spindle assembly checkpoint activation (Nilsson et al, 2008) as has been observed in other organisms (Pan and Chen, 2004). Although the details of this mechanism remain to be clarified, the dissociation rate of the MCC:APC/C complex more than the mechanism per se, modulates the balance of inhibition and release and determines the basis for single kinetochore sensitivity and the timing of spindle assembly checkpoint inactivation. Inhibitor generation has also been implicated within the cytoplasm in which the Mad2:Cdc20 complex generated at the unattached kinetochore, which also contains a Closed (or N2) Mad2 molecule, can induce Mad2 activation by dimerization. Through this reaction, it can hypothetically act to generate new active Mad2 in the cytoplasm through an autocatalytic loop (De Antoni et al, 2005). Such activity has been observed in vitro, but not yet in vivo (Simonetta et al, 2009). Such a cytoplasmic amplification could act as a non-kinetochore source of Mad2:Cdc20 complexes to aid in inhibition of the APC/C (Figure 2D). The combination of the dissociation of the inhibitory complex and the non-kinetochore-mediated generation of APC/C inhibitors underscores the complex role of the cytoplasmic module in checkpoint activation and silencing. Together, these modules identify the critical interfaces by which the kinetochore, microtubules and the cytoplasm exchange information to determine spindle assembly checkpoint activity. As described below, quantitative measurements and computational modelling efforts have focused on these interfaces to provide insight into the dynamics that regulate this pathway. Quantitative observations of spindle assembly checkpoint activity The scarcity of quantitative data often hinders the understanding of cellular systems from a systems perspective. The spindle assembly checkpoint, however, is a notable exception. This field has amassed a substantial amount of quantitative data, on which mathematical models have developed. In this section, we will review some of the most significant quantitative data available for the spindle assembly checkpoint, whereas in the next section, we will describe how these data have been used by modellers to provide a systems perspective of the spindle assembly checkpoint. APC/C reactivation kinetics The timing of mitosis and in particular anaphase onset has been the subject of study for over a century (reviewed in Mazia, 1961). The delay of anaphase with respect to the attachment of the last kinetochore was measured in detail by seminal experiments of Rieder and colleagues. Rieder placed the timing of last kinetochore attachment to anaphase onset at ∼25 min by observation of rat kangaroo (Potorous tridactylus) kidney epithelia cells (Rieder et al, 1995). This interval spans a number of key biochemical steps: (1) the release of APC/C inhibition, (2) ubiquitination and degradation of cyclin B and securin, (3) activation of separase, (4) degradation of cohesin and (5) initiation of the anaphase movements. As such, we can place the reactivation time of the APC/C at a" @default.
W2109322693 created "2016-06-24" @default.
W2109322693 creator A5000474146 @default.
W2109322693 creator A5014808222 @default.
W2109322693 date "2009-07-23" @default.
W2109322693 modified "2023-10-06" @default.
W2109322693 title "A quantitative systems view of the spindle assembly checkpoint" @default.
W2109322693 cites W1483395792 @default.
W2109322693 cites W1890230065 @default.
W2109322693 cites W1963750681 @default.
W2109322693 cites W1965475092 @default.
W2109322693 cites W1966773208 @default.
W2109322693 cites W1967115753 @default.
W2109322693 cites W1967696278 @default.
W2109322693 cites W1969873424 @default.
W2109322693 cites W1971727132 @default.
W2109322693 cites W1973916918 @default.
W2109322693 cites W1975648894 @default.
W2109322693 cites W1978303769 @default.
W2109322693 cites W1980487829 @default.
W2109322693 cites W1980779852 @default.
W2109322693 cites W1982341304 @default.
W2109322693 cites W1991101546 @default.
W2109322693 cites W1999660491 @default.
W2109322693 cites W2001110139 @default.
W2109322693 cites W2005717642 @default.
W2109322693 cites W2007388359 @default.
W2109322693 cites W2008486592 @default.
W2109322693 cites W2008754850 @default.
W2109322693 cites W2010445459 @default.
W2109322693 cites W2011410033 @default.
W2109322693 cites W2012173473 @default.
W2109322693 cites W2015187344 @default.
W2109322693 cites W2015754578 @default.
W2109322693 cites W2015851881 @default.
W2109322693 cites W2016019304 @default.
W2109322693 cites W2018711267 @default.
W2109322693 cites W2029158215 @default.
W2109322693 cites W2032700586 @default.
W2109322693 cites W2037533459 @default.
W2109322693 cites W2042231416 @default.
W2109322693 cites W2045628352 @default.
W2109322693 cites W2048735610 @default.
W2109322693 cites W2048938594 @default.
W2109322693 cites W2050415386 @default.
W2109322693 cites W2062117947 @default.
W2109322693 cites W2065949669 @default.
W2109322693 cites W2067681457 @default.
W2109322693 cites W2071156666 @default.
W2109322693 cites W2071259832 @default.
W2109322693 cites W2074548610 @default.
W2109322693 cites W2076650991 @default.
W2109322693 cites W2078358000 @default.
W2109322693 cites W2079086447 @default.
W2109322693 cites W2082723977 @default.
W2109322693 cites W2084346084 @default.
W2109322693 cites W2087625931 @default.
W2109322693 cites W2088006036 @default.
W2109322693 cites W2088873642 @default.
W2109322693 cites W2089193589 @default.
W2109322693 cites W2089844705 @default.
W2109322693 cites W2097973787 @default.
W2109322693 cites W2102230270 @default.
W2109322693 cites W2104458086 @default.
W2109322693 cites W2106285650 @default.
W2109322693 cites W2106869142 @default.
W2109322693 cites W2108626462 @default.
W2109322693 cites W2114460232 @default.
W2109322693 cites W2114638000 @default.
W2109322693 cites W2114705132 @default.
W2109322693 cites W2119904249 @default.
W2109322693 cites W2124621918 @default.
W2109322693 cites W2127315808 @default.
W2109322693 cites W2127975742 @default.
W2109322693 cites W2128626625 @default.
W2109322693 cites W2132254318 @default.
W2109322693 cites W2132903556 @default.
W2109322693 cites W2137984821 @default.
W2109322693 cites W2139009573 @default.
W2109322693 cites W2139141152 @default.
W2109322693 cites W2142919879 @default.
W2109322693 cites W2143471239 @default.
W2109322693 cites W2144474508 @default.
W2109322693 cites W2151248947 @default.
W2109322693 cites W2157672693 @default.
W2109322693 cites W2161013228 @default.
W2109322693 cites W2163571710 @default.
W2109322693 cites W2164589964 @default.
W2109322693 cites W2166102124 @default.
W2109322693 cites W2167210048 @default.
W2109322693 cites W2170709814 @default.
W2109322693 cites W2171845884 @default.
W2109322693 cites W2186523096 @default.
W2109322693 cites W2258281343 @default.
W2109322693 cites W3213522046 @default.
W2109322693 cites W4233675180 @default.
W2109322693 doi "https://doi.org/10.1038/emboj.2009.186" @default.
W2109322693 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2722251" @default.