Signalling ballet in space and time
Abstract.
Although we have amassed extensive catalogues of signalling network components, our understanding of the
spatiotemporal control of emergent network structures has lagged behind. Dynamic behaviour is starting to be explored throughout the genome, but analysis of spatial behaviours is still confined to individual proteins.
The challenge is to reveal how cells integrate temporal and spatial information to determine specific biological functions. Key findings are the discovery of molecular signalling machines such as Ras nanoclusters, spatial activity gradients and flexible network circuitries that involve transcriptional feedback.
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findings from genome projects have revealed a new problem: there are fewer genes than biological processes. Hence, the concept that the specificity of biological processes is generated on the gene or even protein level erodes.
The idea of isolated pathways has given way to the concept of signalling networks, which allow a limited number of components to generate an exponentially larger number of outcomes owing to combinatorial interactions. Although we now can describe parts of these complex network topologies in detail, we still do not understand how they operate to generate biological specificity. It is like trying to plan a journey with an incomplete railway network map lacking train time schedules. However, biological networks not only transport, but also process and integrate signals. Crucial cell decisions, including whether to undergo proliferation, apoptosis and differentiation, are
governed by the temporal dynamics and spatial distribution of key signalling effectors1–4. This realization provides a strong impetus to explore the emergent properties of signalling networks that are
encoded by spatial and temporal dynamics.
Spatiotemporal control of information.
In addition to the temporal kinetic specification of network function, spatial control plays a major and complementary part. Our trains may leave at the same time but go to different destinations, or leave at different times heading for the same destination. Although the spatial component is less studied than the temporal one, its importance is highlighted by new findings.
Importantly, the transmission of spatial information is controlled by feedback and feed-forward network motifs and cell shape104,109,110
Scaffolds: managers of spatiotemporal organization
The marriage of
spatial and temporal orchestration is embodied in scaffolding proteins. Scaffolds are hallmarked by their ability to simultaneously bind two or more signalling proteins that typically have an enzyme–substrate relationship. The physical colocalization generates interesting properties, such as insulating signalling modules by physically tying them together, reducing reaction kinetics to zero order, enabling immediate feedback and anchoring protein complexes to distinct subcellular sites. Importantly, scaffolds allow the re-use of enzymes for different functions in a highly context-dependent manner, providing a simple solution to the dilemma of possessing fewer genes than processes.
The function of scaffolds in other systems, such as the MAPK pathway, is increasingly being appreciated and was also recently reviewed45–47. Here, we focus on open questions and try to delineate the design principles of how scaffolds contribute to spatiotemporal organization of signalling networks. To illustrate this, we use two examples (FIG. 3).
Given the similarity between the Ras and GPI-anchored nanocluster systems, it is tempting to speculate that this type of analogue–digital–analogue circuitry may represent a general mechanism for high fidelity signal transmission by lipid-anchored signalling proteins.
Similarly to Ras, GPI-anchored proteins also show a fixed monomer to cluster distribution that violates simple mass action kinetics. Recent work has shown that this distribution is actively maintained and crucially dependent on cortical actin dynamics84. More broadly, the role of the unique architecture of the plasma membrane in supporting the assembly of analogue–digital–analogue converters brings into focus membrane spatiotemporal dynamics as a new regulator of signal transmission.
Conclusions.
We have changed our perception of signalling pathways from linear pipelines to networks. We also have begun to rationalize how these network structures can determine the kinetics of distinct biochemical processes with high fidelity to translate them into specific biological responses.
Along this way we have realized that specificity is generated by combinatorial assemblies and spatiotemporal dynamics rather than by a large number of genes with specific functions. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2977972/