title: Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis.
abstract: Signal-transduction networks can display complex dynamic behavior such as oscillations in the activity of key components [1-6], but it is often unclear whether such dynamic complexity is actually important for the network's regulatory functions [7, 8]. Here, we found that the mitogen-activated protein kinase (MAPK) Fus3, a key regulator of the yeast mating-pheromone response, undergoes sustained oscillations in its phosphorylation and activation state during continuous pheromone exposure. These MAPK activity oscillations led to corresponding oscillations in mating-gene expression. Oscillations in MAPK activity and gene expression required the negative regulator of G protein signaling Sst2 and partially required the MAPK phosphatase Msg5. Peaks in Fus3 activation correlated with periodic rounds of cell morphogenesis, with each peak preceding the formation of an additional mating projection. Preventing projection formation did not eliminate MAPK oscillation, but preventing MAPK oscillation blocked the formation of additional projections. A mathematical model was developed that reproduced several features of the observed oscillatory dynamics. These observations demonstrate a role for MAPK activity oscillation in driving a periodic downstream response and explain how the pheromone signaling pathway, previously thought to desensitize after 1-3 hr, controls morphology changes that continue for a much longer time.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Hilioti
authors.forename: Walid
authors.initials: W
authors.lastname: Sabbagh
authors.forename: Saurabh
authors.initials: S
authors.lastname: Paliwal
authors.forename: Adriel
authors.initials: A
authors.lastname: Bergmann
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Goncalves
authors.forename: Lee
authors.initials: L
authors.lastname: Bardwell
authors.forename: Andre
authors.initials: A
authors.lastname: Levchenko
mesh_terms: D001683:Biological Clocks; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009024:Morphogenesis; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D020710:RGS Proteins
chemical_list: D020690:GTPase-Activating Proteins; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D029701:Saccharomyces cerevisiae Proteins; C094301:SST2 protein, S cerevisiae; D020710:RGS Proteins; C075580:FUS3 protein, S cerevisiae; C085791:MSG5 protein, S cerevisiae