Spatial feedback: the final frontier in signaling network motifs?

Cell division is triggered by the temporally abrupt activation of Cdk1-cyclin B1 protein complexes and temporally abrupt spatial redistribution of the complexes from the cytoplasm to the nucleus. Positive feedback loops control the switch-activation of Cdk1-cyclin B1 at the onset of cell division and a study published in Cell on June 22 showed that cells can use the same control strategy for regulation of Cdk1:cyclin B1 intracellular localization: positive feedback regulation. Santos and colleagues show that cyclin B1 phosphorylation promotes nuclear translocation, and nuclear translocation promotes cyclin B1 phosphorylation. This spatial positive feedback ensures a rapid, synchronous, and irreversible cell division.

HFSP Long-Term Fellow Sylvia Santos and colleagues
authored on Mon, 09 July 2012

Cell division is one of the most dramatic events in cell biology. At the onset of mitosis, the terminal phase of the cell cycle, a cell changes from flat to round, condenses its chromosomes, undergoes nuclear envelope breakdown, and reorganizes its microtubules into a spindle, as it gets ready to segregate its newly replicated chromosomes reliably. The transition to mitosis is temporally abrupt, all-or-none in character, and irreversible and at the heart of triggering mitosis is one sole master regulator: the protein complex Cdk1-cyclin B1. Mitosis is triggered by the switch-like activation of Cdk1-cyclin B1 and its abrupt spatial redistribution from the cytoplasm to the nucleus. Positive feedback loops regulate the switch-activation of Cdk1-cyclin B1 and in a study published on June 22 2012 in Cell, Santos et al examined whether an analogous process, spatial positive feedback, could regulate the abrupt Cdk1-cyclin B1 nuclear translocation; whether, in the same way that activation of Cdk1-cyclin B1 promotes its own activation, localization of the Cdk1-cyclin B1 promotes its own localization.

Figure:  Spatial feedback promotes the onset of cell division.
This figure was adapted from the graphical abstract of Santos, SDM et al (2012) Cell (149) 1500:1513

Using multidisciplinary approaches combining mathematical modeling, chemical biology approaches and live cell microscopy, the authors found that nuclear Cdk1-cyclin B1 promotes the translocation of Cdk1-cyclin B1 to the nucleus. Mechanistic studies suggested that cyclin B1 phosphorylation promotes nuclear translocation and, conversely, nuclear translocation promotes cyclin B1 phosphorylation, accounting for the spatial feedback logic. Phosphorylated cyclin B1 was found to co-localize to condensed chromatin raising the interesting possibility that phosphorylation enhances both the nuclear import and nuclear residency of the Cdk1-cyclin B1 complex. Interfering with the abruptness of Cdk1-cyclin B1 translocation affects the timing and synchronicity of subsequent mitotic events, arguing that the switch-like initiation of mitosis is important for the ordering, uni-directionality and successful completion of mitotic events.

This study shows that spatial positive feedback ensures a rapid, complete, robust and irreversible mitotic onset. The authors propose that the combined, interlinked positive feedback in both Cdk1-cyclin B1 activation and Cdk1-cyclin B1 localization may be more robust and reliable in triggering a well-coordinated mitotic entry than the individual loops would be by themselves.

One of the most important steps forward in our understanding of the systems biology of cellular regulation has been the appreciation that there are recurrent motifs that define how proteins regulate each other’s activities. However protein function is regulated not only through temporal regulation of activity, but also through the regulation of localization. The present work shows positive feedback, a motif found in many signaling pathways, can also be an important design principle in the control of protein localization. Given how common it is for regulatory proteins to rapidly translocate from the cytoplasm to the nucleus in response to stimuli, it is conceivable that spatial positive feedback may be a recurring theme in spatial-temporal switches in intracellular regulation.

Reference

Spatial Positive Feedback at the Onset of Mitosis. Silvia D.M. Santos, Roy Wollman, Tobias Meyer, James E. Ferrell Jr. Cell, Volume 149, Issue 7, 22 June 2012, Pages 1500-1513

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