Negative feedback that improves information transmission in yeast signalling.

Haploid Saccharomyces cerevisiae yeast cells use a prototypic cell signalling system to transmit information about the extracellular concentration of mating pheromone secreted by potential mating partners. The ability of cells to respond distinguishably to different pheromone concentrations depends on how much information about pheromone concentration the system can transmit. Here we show that the mitogen-activated protein kinase Fus3 mediates fast-acting negative feedback that adjusts the dose response of the downstream system response to match the dose response of receptor-ligand binding. This 'dose-response alignment', defined by a linear relationship between receptor occupancy and downstream response, can improve the fidelity of information transmission by making downstream responses corresponding to different receptor occupancies more distinguishable and reducing amplification of stochastic noise during signal transmission. We also show that one target of the feedback is a previously uncharacterized signal-promoting function of the regulator of G-protein signalling protein Sst2. Our work suggests that negative feedback is a general mechanism used in signalling systems to align dose responses and thereby increase the fidelity of information transmission.

Automatic generation of cellular reaction networks with Moleculizer 1.0.

Accurate simulation of intracellular biochemical networks is essential to furthering our understanding of biological system behavior. The number of protein complexes and of chemical interactions among them has traditionally posed significant problems for simulation algorithms. Here we describe an approach to the exact stochastic simulation of biochemical networks that emphasizes the contribution of protein complexes to these systems. This simulation approach starts from a description of monomeric proteins and specifications for binding, unbinding and other reactions. This manageable specification is reasonably intuitive for biologists. Rather than requiring the inclusion of all possible complexes and reactions from the outset, our approach incorporates new complexes and reactions only when needed as the simulation proceeds. As a result, the simulation generates much smaller reaction networks, which can be exported to other simulators for further analysis. We apply this approach to the automatic generation of reaction systems for the study of signal transduction networks.

Pathfinder and other tools for analyzing signal transduction networks.

Many electronic design tools are, at their core, tools for analyzing interacting networks of components in which there is a definite causal sense of direction in each interaction: outputs affect inputs, but not vice versa. Simplifying or restricting a network of protein interactions so that this kind of directedness holds makes the same category of software tools applicable. In signal transduction cascades the direction is usually given by "kinase phosphorylates substrate." This paper examines a few kinds of directed network analysis tools in the context of signal transduction.

Software for signaling networks, electronic and cellular.

Cellular signaling networks have many similarities with electronic circuits. Therefore, the tools used to test and analyze electronic circuits can be adapted to analyze cellular signaling processes. Lok describes some of these signaling network analysis tools, their underlying principles, and their limitations.