Information processing in a cell fate decision system

ALEJANDRO COLMAN LERNER

Bariloche

Congreso; SISTAM2018; 2018

SISTAM

Cell behavior requires the ability to detect and respond to extracellular signals. We usethe response to mating pheromone in the budding yeast S. cerevisiae as a model system. Iwill present recent work that addresses two general problems signaling pathways mustsolve: eliciting robust responses despite large variability in cellular components andappropriate integration of extracellular and intracellular signals.Robustness: The effect of ligands usually depends on the amount of ligand-receptorcomplex. Thus, changes in receptor abundance should have quantitative effects.However, the response to pheromone in yeast is robust (unaltered) to variation in theabundance of the GPCR receptor, Ste2, responding instead to the fraction of occupiedreceptor. To learn how fractional occupancy is measured by the cell, we developed amathematical model of GPCR activation, which suggested that the ability to computefractional occupancy depended on the physical interaction between the inhibitory RGS,Sst2, and the receptor. I will present here the experimental evidence that supports thismodel and explain how it might apply to other GPCR systems and to signal transductionpathways in general.Signal integration: The pheromone pathway has an antagonistic relationship with the cellcycle. The pathway MAPK (Fus3) arrests the cell cycle by activating a CDK inhibitor.Conversely, when cells pass START, the CDK (Cln2-Cdc28) blocks pheromone response byphosphorylating the scaffold protein Ste5, which prevents its association with the plasmamembrane. We found that efficient Cln2-Cdc28 inhibition of Ste5 requires the help ofFus3. This is surprising since previous literature suggested that CDK should be able to dothe blocking by itself. However, our results thus show that Fus3, which usually serves topromote mating, also serves to block mating during the wrong part of the cell cycle. Wemade this discovery thanks to our ability to perform fast single cell measurement of Ste5membrane recruitment in a large number of mutant strains. This approach, incombination with analyses of Ste5 phosphorylation via gel mobility assays andquantitative mass-spectrometry, led us to propose a detailed molecular model that I willpresent here to explain this unexpected MAPK-CDK collaboration.