Triggering the all-or-nothing switch into mitosis

Abstract

The past decade of cell cycle investigations has identified many roads not taken. The kinase that drives mitosis can be modulated by cyclins, by activating phosphorylation, by inhibitory phosphorylation and by binding of inhibitors, but one of these regulatory options controls the transition from G2 phase to mitosis in most circumstances. A switch-like mechanism integrates signals of cellular status and commits the cell to mitosis by abruptly removing inhibitory phosphate from preformed cyclin:Cdk1 complexes. The pathways that flip this switch alter the balance of modifying reactions to favor dephosphorylation, thereby generating a flood of mitotic kinase.

Fig. 1

Major cell cycle transitions show all-or-nothing regulation. Switch-like events regulate the accumulation, activity or destruction of cyclin:CDK complexes to drive the key transitions of the cell cycle. The circuitry that creates switch-like behavior is incompletely understood, but the G1:S phase transition and the initiation of anaphase are associated with abrupt and important changes in the activity of the ubiquitination complexes APC and SCF that target proteins for degradation. The partially characterized switch that governs the G2:M transition changes the activities of Cdk1-modifying enzymes to abruptly relieve the inhibition of Cdk1 activity that characterizes G2.

Fig. 2

Tiers of Cdk1 regulation. The signals controlling Cdk1 flow through several regulatory tiers (colors). At the most immediate level (orange), Cdk1 is regulated by cyclin association, by activating phosphorylation on T161, by association with cyclin:kinase inhibitory proteins (CKIs) and by inhibitory phosphorylation on T14 and/or Y15. These immediate regulators include inducers, whose action is indicated with pointed arrows, or inhibitors, whose action is indicated by ‘arrows’ ending in a bar. In turn, these immediate regulators are regulated by upstream factors (turquoise). Cyclin levels are controlled at the levels of synthesis and APC-promoted destruction. The CKIs that have important regulatory inputs into Cdk1, such as Sic1 of Saccharomyces cerevisiae, Rum1 of Schizosaccharomyces pombe and RUX1 of Drosophila, are inactivated by CDK activity (mutual antagonism). The components that are involved in the mitotic switch are clustered towards the top of the diagram. Regulators of inhibitory phosphorylation (Myt1 and Wee kinases, and Cdc25 phosphatase) are subject to elaborate regulation (gold arrows). These pathways flip the mitotic switch at the appropriate time. Importantly, in organisms from yeast to humans, the predominant regulatory paths used to govern entry into mitosis act through the regulators of inhibitory phosphorylation. These regulators appear to be specialized for controlling this transition. They have conserved regulatory inter-relationships that impart the switch-like behavior on the transition into mitosis. Note that specialization of some gene family members (e.g. Wee1 and Mik1 of S. pombe) complicates some of the generic generalizations made here. Abbreviation: MAP kinase, mitogen-activated protein kinase.

Fig. 3

Positive feedback contributes to the mitotic switch. Activation of Cdc25 phosphatase and inhibition of the inhibitory kinase Wee1 contribute to the all-or-nothing behavior of Cdk1 activation at the entry to mitosis. Although Cdk1 phosphorylates its own modifying enzymes, the details of the regulatory loops are still incompletely understood (Box 3). The basic relationships described in this diagram have been conserved from yeast to human and apply to a second inhibitory kinase, Myt1, as well as to Wee1.