Fig. 4. A feed-forward loop underlies CDK2 reversibility.
a, Textbook model of the signalling pathway showing that cyclin A2 levels and CDK2 activity can be continuously maintained independent of mitogen signalling due to the proposed CDK2–Rb feedback loop. b, Revised model showing a feed-forward signalling pathway where mitogen signalling continuously maintains cyclin A2 and CDK2 activity in post-R cells. c, Output from mathematical modelling of the feedback loop model in a after mitogen removal. Cyclin A2 levels and CDK2 activity remain high. d, Output from mathematical modelling of the feed-forward pathway model in b after mitogen removal. Cyclin A2 levels and CDK2 activity appear irreversible at the time cells normally enter mitosis, although they eventually reach a steady state of zero, explaining why cells exit the cell cycle. e, CDK2 activity levels for pre- and post-R cells with respect to mitogen concentration for the feedback loop model (top panel) and the feed-forward pathway model (middle panel) at the indicated times after simulated change in mitogens. The observed (bottom panel) dose response relationship between CDK2 activity and MEKi concentration for pre- and post-R cells is shown. CDK2 activity was evaluated after MEKi treatment at the times indicated. Mitosis was blocked using a CDK1i. Error bars are s.e.m. from n = 2 replicates. f, For MCF-10A cells, in the absence of mitogens, competition between mitosis and cell cycle exit determines the fate of the cell due to a feed-forward loop regulating cyclin A2. A cell that is greater than approximately 15 h away from mitosis at the time mitogen signalling is blocked (cell 1) will lose cyclin A2 and exit, while a cell further along the cell cycle (cell 2) will reach mitosis before it will lose cyclin A2 and divide into two daughter cells.