Coordination of MAP Kinase Signaling During Cell Fate Decisions

Nagiec, Michal

Download PDF

Request Version for Screen Reader

Last Modified

March 22, 2019

Creator

Nagiec, Michal
- Affiliation: School of Medicine, Department of Pharmacology

Abstract

Cells detect and respond to a wide diversity of environmental signals. These signals commonly stimulate mitogen-activated protein kinase (MAPK) pathways that evoke a cellular response. Particular environmental signals generate MAPK responses that are mutually exclusive. The coordination of competing MAPK signals is required to produce an appropriate cell fate. Budding yeast, Saccharomyces cerevisiae, use MAPK pathways to respond to developmental signals and environmental stress. Mating pheromones initiate the mating response pathway, which promotes mating differentiation. Hyperosmotic stress initiates the high osmolarity stress (HOG) response pathway, which promotes stress adaptation. The two pathways share components despite producing competing cell fates. Here we describe mechanisms that coordinate MAPK signaling to ensure proper cell fate decisions. We studied how the mating MAPK Fus3 and the HOG MAPK, Hog1 are coordinated in co-stimulated cells. We find that stress adaptation takes precedence over mating differentiation by two Hog1-dependent mechanisms. First, Hog1 phosphorylates the protein kinase, Rck2, and thereby inhibits pheromone-induced protein translation. Second, Hog1 phosphorylates a shared pathway component, Ste50, and thereby dampens pheromone-induced MAPK activation. These findings point to two mechanisms of cross-pathway inhibition used by one MAPK to coordinate the activity of a second, competing MAPK. We also studied the coordination that occurs between the two MAPKs activated by mating pheromones, Fus3 and Kss1. Both MAPKs have roles in mating however Kss1 also promotes filamentous growth in response to poor nutrient conditions. Thus, coordination of Fus3 and Kss1 is critical to maintaining proper mating differentiation. We find that Fus3 phosphorylates a shared pathway component Ste7 to diminish Kss1 activity and prevent aberrant filamentous growth during the mating response. The study of mechanisms that determine cell fate in yeast might provide insights about signal coordination and attenuation in more complex eukaryotic MAPK pathways. Our analysis reveal that feedback phosphorylation of shared components contribute to the coordination of MAPK activity. The insights gained from this work could contribute to discovery of new therapies, specifically for disease where MAPK pathways are hyperactivated.

Date of publication