Ydenberg and Rose show that yeast cells use both pheromone signaling and the cell cycle to ensure that a protein important for mating only operates at the right time and place.

When haploid yeast cells sense pheromones from an opposite mating type, they differentiate by inducing expression of mating-specific genes, arresting in the G1 phase of the cell cycle, and sending out protrusions called “shmoos” toward the source of the pheromone. One induced protein, Fus2p, initially localizes to the nucleus but moves to the shmoo tip after cell cycle arrest to mediate mating-cell fusion. Fus2p's expression and localization depends on the pheromone-activated MAP kinase Fus3p. But how Fus3p targets Fus2p to the shmoo tip, and why this only occurs after G1 arrest was unknown.

Ydenberg and Rose found that Fus3p directly phosphorylated Fus2p to promote its localization to the cytoplasm, but Fus2p always remained nuclear until after cell division. The cell cycle–regulated, cyclin-dependent kinase Cdc28p modulates the yeast response to pheromones, so the authors reasoned that it might control Fus2p's whereabouts by counteracting Fus3p. Indeed, they found that Cdc28p opposes Fus3p in two different ways, depending on which stage of the cell cycle the yeast are at.

In late G1 and S phase, it was already known that Cdc28p prevented the activation of Fus3p by pheromones. Later in the cell cycle, at G2/M phase, pheromone signaling and Fus3p were fully active but Cdc28p still prevented Fus2p from exiting the nucleus by an unknown mechanism. Only after cell division and G1 arrest was Cdc28p activity low enough for Fus3p to promote Fus2p's redistribution to the cytoplasm and shmoo tip.

Why do yeast regulate Fus2p's localization using both pheromone and cell cycle–regulated pathways? Ydenberg and Rose think that it may be vital for Fus2p to remain sequestered in the nucleus until after cell division so that it can't interfere with cytokinesis: Fus2p is likely to be an activator of Rho GTPases, so localizing it to the wrong place at the wrong time might have disastrous consequences for the cell. Differentiating cells in higher eukaryotes face similar problems as they turn on genes not normally expressed during the mitotic cycle. To safely differentiate, the authors suspect that other eukaryotes have evolved similar solutions to those used by mating yeast.

J. Cell Biol.