Control of Membrane Localization

Pheromone signaling arrests cells in G1 phase, prior to the cell cycle commitment point called “Start”. But once cells pass Start, pheromone signaling is inhibited by the action of CDKs. We found that the target of this inhibition is Ste5. Specifically, CDKs phosphorylate Ste5 at multiple sites flanking the membrane-binding PM domain, thereby disrupting membrane association. If these sites are mutated to non-phosphorylatable residues (Ste5-8A), then signaling cannot be inhibited during cell cycle progression. Of note, phosphorylation at these sites exerts bulk electrostatic effects such that the magnitude of the inhibitoryeffect is proportional to the number of phosphates added. That is, there is a regulatory continuum in which partial phosphorylation yields only partial inhibition.This characteristic creates opportunities for regulatory diversity in which signaling can be modulated to varying degrees, or perhaps in concert with other regulatory inputs. Such possibilities are being explored in our current studies.

Relevant Publications

Winters MJ, Pryciak PM. MAPK modulation of yeast pheromone signaling output and the role of phosphorylation sites in the scaffold protein Ste5. Mol Biol Cell. 2019 Apr 1;30(8):1037-1049. doi: 10.1091/mbc.E18-12-0793. Epub 2019 Feb 6. PMID: 30726174; PMCID: PMC6589907.

Repetto MV, Winters MJ, Bush A, Reiter W, Hollenstein DM, Ammerer G, Pryciak PM, Colman-Lerner A. CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5. Mol Cell. 2018 Mar 15;69(6):938-952.e6. doi: 10.1016/j.molcel.2018.02.018. PMID: 29547722; PMCID: PMC5858200.