Mechanisms that coordinate cell size and mitotic entry

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A wide variety of cell types delay cell cycle transitions until they reach a critical size threshold, but the mechanisms that measure size and transmit this information to the core cell cycle machinery are largely unknown. Fission yeast cells divide at a specific surface area due to signaling by large, multi-protein structures called “nodes” at the cortex. Nodes contain conserved cell cycle regulators including the protein kinases Cdr2, Cdr1, and Wee1, which function in a linear, genetically defined pathway to regulate mitotic entry. Recently, we discovered that nodes also contain the conserved GTPase Arf6 and found that Arf6 promotes mitotic entry through the Cdr2- Cdr1-Wee1 pathway. We do not know the mechanisms of assembly or signal transduction within nodes. We will address key open questions using powerful genetic, biochemical, and quantitative imaging approaches. Mutations that abolish node signaling cause cells to divide at a specific volume, as opposed to surface area. Based on several lines of evidence, we hypothesize that regulated accumulation of Cdc25 in the cell nucleus represents the volume sensor. We will test the model that cell size control emerges from different pathways, each monitoring distinct aspects of cell geometry. We will focus on the fundamental process of cell cycle regulation, but our work has broad implications for spatial control of signal transduction because higher-order clusters and node-like structures are emerging as critical sites of signal transduction throughout cell biology. The specific aims of this grant are to: (1) define the molecular mechanism of Cdr2 node assembly and function, (2) determine how Arf6 GTPase regulates Cdr2 nodes and cell size at division, and (3) test the model that Cdc25 and Cdr2 pathways monitor distinct aspects of cell geometry. Successful completion of these goals will advance scientific knowledge by identifying how defined signaling pathways respond to different aspects of cell growth. Moreover, the signaling mechanisms that we uncover will provide insights for how size controls the activity of other biological systems.