Diverse sensitivity thresholds in dynamic signaling responses by social amoebae.

The complex transition from a single-cell to a multicellular life form during the formation of a fruiting body by the amoeba Dictyostelium discoideum is accompanied by a pulsatile collective signaling process that instigates chemotaxis of the constituent cells. Although the cells used for the analysis of this phenomenon are normally genetically identical (isogenic), it is not clear whether they are equally responsive to the waves of the signaling stimulus, nor is it clear how responses across the population influence collective cell behavior. Here, we found that isogenic Dictyostelium cells displayed differing sensitivities to the chemoattractant cyclic adenosine monophosphate (cAMP). Furthermore, the resulting signaling responses could be explained by a model in which cells are refractory to further stimulation for 5 to 6 min after the initial input and the signaling output is amplified, with the amplification threshold varying across the cells in the population. This pathway structure could explain intracellular amplification of the chemoattractant gradient during cell migration. The new model predicts that diverse cell responsiveness can facilitate collective cell behavior, specifically due to the presence of a small number of cells in the population with increased responsiveness that aid in propagating the initial cAMP signaling wave across the cell population.

A scalable and integrative system for pathway bioinformatics and systems biology.

MOTIVATION: Progress in systems biology depends on developing scalable informatics tools to predictively model, visualize, and flexibly store information about complex biological systems. Scalability of these tools, as well as their ability to integrate within larger frameworks of evolving tools, is critical to address the multi-scale and size complexity of biological systems. RESULTS: Using current software technology, such as self-generation of database and object code from UML schemas, facilitates rapid updating of a scalable expert assistance system for modeling biological pathways. Distribution of key components along with connectivity to external data sources and analysis tools is achieved via a web service interface. AVAILABILITY: All sigmoid modeling software components and supplementary information are available through: http://www.igb.uci.edu/servers/sb.html.

Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis.

Signal-transduction networks can display complex dynamic behavior such as oscillations in the activity of key components [1-6], but it is often unclear whether such dynamic complexity is actually important for the network's regulatory functions [7, 8]. Here, we found that the mitogen-activated protein kinase (MAPK) Fus3, a key regulator of the yeast mating-pheromone response, undergoes sustained oscillations in its phosphorylation and activation state during continuous pheromone exposure. These MAPK activity oscillations led to corresponding oscillations in mating-gene expression. Oscillations in MAPK activity and gene expression required the negative regulator of G protein signaling Sst2 and partially required the MAPK phosphatase Msg5. Peaks in Fus3 activation correlated with periodic rounds of cell morphogenesis, with each peak preceding the formation of an additional mating projection. Preventing projection formation did not eliminate MAPK oscillation, but preventing MAPK oscillation blocked the formation of additional projections. A mathematical model was developed that reproduced several features of the observed oscillatory dynamics. These observations demonstrate a role for MAPK activity oscillation in driving a periodic downstream response and explain how the pheromone signaling pathway, previously thought to desensitize after 1-3 hr, controls morphology changes that continue for a much longer time.

Transient IkappaB kinase activity mediates temporal NF-kappaB dynamics in response to a wide range of tumor necrosis factor-alpha doses.

Dynamic properties of signaling pathways control their behavior and function. We undertook an iterative computational and experimental investigation of the dynamic properties of tumor necrosis factor (TNF)alpha-mediated activation of the transcription factor NF-kappaB. Surprisingly, we found that the temporal profile of the NF-kappaB activity is invariant to the TNFalpha dose. We reverse engineered a computational model of the signaling pathway to identify mechanisms that impart this important response characteristic, thus predicting that the IKK activity profile must transiently peak at all TNFalpha doses to generate the observed NF-kappaB dynamics. Experimental confirmation of this prediction emphasizes the importance of mechanisms that rapidly down-regulate IKK following TNFalpha activation. A refined computational model further revealed signaling characteristics that ensure robust TNFalpha-mediated cell-cell communication over considerable distances, allowing for fidelity of cellular inflammatory responses in infected tissue.