Editors' ChoicePheromone signaling

Meaningful Fluctuations

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Science Signaling  18 Nov 2008:
Vol. 1, Issue 46, pp. ec396
DOI: 10.1126/scisignal.146ec396

Pheromones trigger the phosphorylation and activation of the yeast mitogen-activated protein kinases (MAPKs) Fus3 and Kss1 through a G protein–coupled receptor (GPCR) pathway. Previous studies indicated that MAPK activity returns to baseline shortly after pheromone activation as a result of GPCR desensitization. Noting that physiological responses to pheromone stimulation can sometimes last several hours, Hilioti et al. used Fus3 or Kss1 phosphorylation status as an indicator of MAPK activity over longer periods of pheromone exposure than had been previously studied. As expected, the amounts of phosphorylated Fus3 and Kss1 peaked and returned to baseline shortly after pheromone stimulation was initiated, but surprisingly, they increased again to near-peak levels with continued pheromone exposure. In yeast expressing a Fus3-green fluorescent protein (Fus3-GFP), the amounts of phosphorylated Fus3-GFP and Kss-1, as well as the total amount of Fus3-GFP, rose and fell three times over 8 hours of continuous pheromone stimulation. Prolonged pheromone stimulation can trigger the formation more than one mating projection, and Hilioti et al. showed that oscillations in phosphorylated and total amounts of Fus3-GFP appeared to drive the formation of multiple mating projections. The appearance of additional mating projections correlated with the number of peaks of MAPK activity, and in the absence of the negative MAPK pathway regulators Sst2 [a regulator of G protein signaling (RGS) protein] or Msg5 (a phosphatase), yeast failed to exhibit MAPK oscillations and only formed a single mating projection during prolonged pheromone exposure. MAPK oscillations did not depend on the formation of mating projections, as a strain of yeast that is incapable of forming mating projections still exhibited oscillations in phosphorylation and abundance of Fus3-GFP. A mathematical model accurately predicted the effect of pheromone dose on the amplitude and phase of MAPK oscillations, as well as oscillations in Sst2 abundance that were at the same frequency as those in Fus3 amounts but shifted in phase. Thus, the oscillations in MAPK activity and abundance that occur in yeast during sustained pheromone stimulation can be correlated with the formation of multiple mating projections, and modeling of the pheromone signaling pathway can account for the factors affecting MAPK oscillations, including pheromone doses and negative regulation.

Z. Hilioti, W. Sabbagh Jr., S. Paliwal, A. Bergmann, M. D. Goncalves, L. Bardwell, A. Levchenko, Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis. Curr. Biol. 18, 1700–1706 (2008). [PubMed]

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