Interaction Dynamics Determine Signaling and Output Pathway Responses

Publication date: 4 April 2017
Source:Cell Reports, Volume 19, Issue 1
Author(s): Klement Stojanovski, Tony Ferrar, Hannah Benisty, Friedemann Uschner, Javier Delgado, Javier Jimenez, Carme Solé, Eulalia de Nadal, Edda Klipp, Francesc Posas, Luis Serrano, Christina Kiel
The understanding of interaction dynamics in signaling pathways can shed light on pathway architecture and provide insights into targets for intervention. Here, we explored the relevance of kinetic rate constants of a key upstream osmosensor in the yeast high-osmolarity glycerol-mitogen-activated protein kinase (HOG-MAPK) pathway to signaling output responses. We created mutant pairs of the Sln1-Ypd1 complex interface that caused major compensating changes in the association (kon) and dissociation (koff) rate constants (kinetic perturbations) but only moderate changes in the overall complex affinity (Kd). Yeast cells carrying a Sln1-Ypd1 mutant pair with moderate increases in kon and koff displayed a lower threshold of HOG pathway activation than wild-type cells. Mutants with higher kon and koff rates gave rise to higher basal signaling and gene expression but impaired osmoadaptation. Thus, the kon and koff rates of the components in the Sln1 osmosensor determine proper signaling dynamics and osmoadaptation.

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Teaser

Understanding how signaling pathways operate is essential for network-based biotechnology and therapeutic approaches. Using the yeast HOG pathway as a model system, Stojanovski et al. show that altered interaction dynamics (association and dissociation rate constants) of the upstream Sln1-Ypd1 sensor cause basal pathway activation, gene expression, and impaired osmoadaptation.


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