The "starter" and "gas pedal" of mitosis reside at the centrosome: Commentary on "Characterization of centrosomal localization and dynamics of CDC25C phosphatase in mitosis" by Bonnet et al.

Abstract

The CDC25 phosphatases play an essential role in the spatial and temporal regulation of the control of entry into mitosis. These enzymes dephosphorylate and activate the CDK-cyclin complexes, in particular CDK1-cyclin B1, the master regulator of mitosis. Three CDC25 genes in exist in humans (CDC25A, CDC25B and CDC25C), and the original model of their function proposed that they acted sequentially at discrete cell cycle transitions, i.e., that CDC25A was dedicated to the activation of the G1/S progression-associated CDKs, CDC25B controlled early prophase events, while CDC25C was thought to achieve the full activation of CDK1-cyclin B1 at entry into mitosis. Indeed, the situation appears much more complicated than this, and current evidence shows that all three CDC25 phosphatases act at a variety of mitotic stages, with and considerable experimental evidence to indicate that all three are involved in orchestrating cell cycle progression in mitosis.1 Previous work has led to the proposal that CDC25B acts as the starter of mitosis. Additionally, a number of recent studies have shown that CDC25B also localizes to the centrosome where its activating role on CDK-cyclin complexes appears to be regulated by multiple activatory and inhibitory kinases.2-5 As such, it has been proposed that CDC25B might act as a central centrosomal integrator and a trigger for the initial events that set up the sequence of events leading to mitosis.6 As a target of the first small pool of activated CDK1-cyclin B1 that translocates to the nucleus, CDC25C was thought to subsequently be responsible for the massive activation of the nuclear pool of CDK1-cyclin B1 that occurs at entry into mitosis. A report from the group headed by May Morris presented in this issue of Cell Cycle (Bonnet et al., pp. 1990–7) provides new insight into the dynamics of these events and in the understanding of the involvement of both CDC25B and CDC25C in the earliest stages of the G2/M transition. Bonnet and collaborators show for the first time, as has long been suspected but until now never observed, the localization of a fraction of CDC25C at the centrosome during interphase. This centrosomal localization occurs from S-phase onward and is also present during mitosis. Using FRAP analysis, their study elegantly shows that this centrosomal population of CDC25C is highly dynamic. Furthermore, the authors show that mutations of CDC25C that impair its catalytic activity or its binding to its CDK-cyclin substrates promote its centrosomal accumulation, thus suggesting an active role in the dephosphorylation and activation of CDK-cyclins at this location. Together with previous reports showing that the activity of CDC25C is amplified following its mitotic phosphorylation by CDK1-cyclin B1 while the activity of CDC25B is not,7 these new findings lead to the proposition of an alternative regulatory model for the control of the G2/M transition. In this model, the CDK1-cyclin B1 complex is activated at the centrosomal level both by the initial action of CDC25B (as has already been suggested8) as well as by the centrosomal pool of activated CDC25C that subsequently amplifies the process through its own phosphorylation and activation (Fig. 1). While CDC25B can be considered as a “starter”, CDC25C plays the role of the “gas pedal” that speeds up entry into mitosis by amplifying the signaling cascade from the centrosome and finally increasing nuclear levels. This model is certainly too simplistic and does not integrate many major issues that remain to be investigated. Among these unsolved questions is the role that the multiple splice variants of the CDC25 phosphatases might play. There are at least five variants for both CDC25B and CDC25C whose specific regulation and roles in the dephosphorylation of individual CDK-cyclins substrates is still unknown.5 Likely related to this question is the issue of the presence of both CDC25B and CDC25C until late stages of mitosis. Why is CDC25C associated with the centrosome when, according to the dogma, the entire pool of CDK1-cyclin B1 has been fully activated? An attractive hypothesis is to speculate that the CDC25 phosphatases might continue to play discrete roles in the dephosphorylation and the activation of sub-populations of CDK-cyclins throughout the entire process of mitosis to ensure a fine tuning of the kinase activities that are involved in the many architectural and functional aspects of the mitotic figure. Centrosomes are made up of numerous proteins whose amino acid sequence suggests a coiled-coil tertiary structure. Increasing evidence indicates that this molecular structure may be well-designed for the organization of multiprotein scaffolds that can anchor a diversity of activities ranging from protein complexes involved in microtubule nucleation to multicomponent pathways for cellular regulation.9 By physically linking components of a common pathway, molecular scaffolds can increase the local concentration of components, limit nonspecific interactions, and provide spatial control for regulatory pathways by positioning by positioning them at specific sites in proximity to downstream targets or upstream modulators. On the basis of the increasing number of regulatory molecules anchored at the centrosome, it is likely that this organelle serves as a centralized control center for regulating a diversity of cellular activities. Recent studies have provided some of the first functional links between centrosomes and regulatory networks in cell cycle transitions from G1 to S-phase, G2 to M-phase and metaphase to anaphase. The findings by Bonnet et al. support this line of evidence.

References

Boutros R, Dozier C, Ducommun B. The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol 2006; 18:185-91. Dutertre S, Cazales M, Quaranta M, Froment C, Trabut V, Dozier C, Mirey G, Bouche J, Theis-Febvre N, Schmitt E, Monsarrat B, Prigent C, Ducommun B. Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2/M transition. J Cell Science 2004; 117:2523-31. Schmitt E, Boutros R, Froment C, Monsarrat B, Ducommun B, Dozier C. CHK1 phosphorylates CDC25B during the cell cycle in the absence of DNA damage. J Cell Sci 2006; 119:4269-75. Boutros R, Ducommun B. Asymmetric localization of the CDC25B phosphatase to the mother centrosome during interphase. Cell Cycle 2008; 7:401-6. Boutros R, Lobjois V, Ducommun B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 2007; 7:495-507. Lindqvist A, Kallstrom H, Lundgren A, Barsoum E, Rosenthal CK. Cdc25B cooperates with Cdc25A to induce mitosis but has a unique role in activating cyclin B1-Cdk1 at the centrosome. J Cell Biol 2005; 171:35-45. Baldin V, Pelpel K, Cazales M, Cans C, Ducommun B. Nuclear Localization of CDC25B1 and Serine 146 Integrity Are Required for Induction of Mitosis. J Biol Chem 2002; 277:35176-82. Jackman M, Lindon C, Nigg EA, Pines J. Active cyclin B1-Cdk1 first appears on centrosomes in prophase. Nat Cell Biol 2003; 5:143-8. Kramer A, Lukas J, Bartek J. Checking out the centrosome. Cell Cycle 2004; 3:1390-3.