Spatial Feedback: The New Frontier Of Signaling Network Motifs

Mitosis is one of the most dramatic events in cell biology and the transition from interphase to mitosis is temporally abrupt, all-or-none in character, and irreversible. Mitosis is triggered by the activation of Cdk1-cyclin B1 and its abrupt translocation 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, Silvia Santos from Jim Ferrell’s lab examined whether an analogous process, spatial positive feedback, could regulate the abrupt Cdk1-cyclin B1 spatial redistribution to the nucleus. Using chemical biology approaches and live cell microscopy, the authors found that nuclear Cdk1-cyclin B1 indeed promotes the translocation of Cdk1-cyclin B1 to the nucleus. Mechanistic studies and mathematical modeling suggested that cyclin B1 phosphorylation promotes nuclear translocation and, conversely, nuclear translocation promotes cyclin B1 phosphorylation, accounting for the spatial feedback. 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 transition from interphase to mitosis.

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.