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  • Published:

Signalling ballet in space and time

Nature Reviews Molecular Cell Biology volume 11, pages 414–426 (2010)Cite this article

Subjects

Key Points

  • Spatiotemporal network dynamics govern cell fate decisions. We use the extracellular signal-regulated kinase (ERK) pathway as a paradigm to describe how temporal activation kinetics and spatial organization control biological decisions.

  • Signalling circuits can operate as analogue-to-digital converters, generating abrupt switches, multistable dynamics, excitable pulses and oscillations. These distinct outputs facilitate signal discrimination by target gene networks and control cell phenotypic responses.

  • The transfer of information through signalling networks is regulated at several levels and includes spatiotemporal control. Multiple regulatory motifs, such as feedback and feed-forward phosphorylation loops, and crosstalk between pathways provide robustness and fidelity of the input–output responses.

  • Scaffolding proteins physically link pathway components, thereby forming signalling modules that markedly affect spatiotemporal control of signalling and specificity of inputs and outputs. Scaffolds often also localize these signalling units to distinct subcellular compartments and can allosterically regulate binding partners.

  • Nanoscale and microscale signalling domains are highly dynamic structures that form in membrane compartments. Well-characterized domains are Ras nanoclusters that may have a crucial control in input–output relationships in the Ras–Raf–MAPK/ERK kinase–ERK pathway.

  • Distinct spatial domains can also arise from chemical reactions coupled with diffusion. Combined with the distinct localization of enzymes, these processes generate intricate concentration landscapes of enzymatic reactivities, macromolecules and second messengers within cells.

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. They reveal design principles of spatiotemporal organization that are crucial for network function and cell fate decisions.

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Figure 1: Versatile MAPK dynamics.
Figure 2: Intrinsic transcriptional feedback inhibition of NF-κB.
Figure 3: Scaffolds and spatial organization.
Figure 4: Ras nanoclusters digitize transmembrane signal transmission.

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Acknowledgements

We thank M. Tsyganov, J. Muñoz García, A. Kiyatkin and N. Kaimachnikov for discussions. This work was supported by Science Foundation Ireland under Grant No. 06/CE/B1129 and National Institutes of Health grants GM059570, GM066717. We apologize about not citing many pertinent contributions to the field because of space limitations.

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Authors and Affiliations

  1. Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland

    Boris N. Kholodenko & Walter Kolch

  2. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA

    Boris N. Kholodenko

  3. Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, 77030, Texas, USA

    John F. Hancock

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  1. Boris N. Kholodenko
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Correspondence to Boris N. Kholodenko.

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Nature pathway interaction database for Ras

Nature pathway interaction database for MEK

Nature pathway interaction database for ERK

Glossary

Temporal dynamics

A quantitative description of how the system's behaviour changes over time.

Pheochromocytoma

An adrenal gland tumour that originates from cells derived from the neural crest.

Adenocarcinoma

A cancer arising in glandular parts of epithelial tissues.

Non-processive

Reaction mechanism in which the reactants dissociate after each partial reaction and have to encounter again for a new reaction. For instance, MEK phosphorylates ERK on two sites in a non-processive reaction that requires two distinct MEK–ERK interactions, in which only one site is phosphorylated per interaction event.

Spatiotemporal dynamics

A description of how the system behaviour changes in space and time.

Perfect adaptation

A term that, in control engineering, indicates the control strategy ensuring that the system output follows the desired course regardless of noise and variations in system parameters.

Damped oscillations

Oscillations the amplitude of which decreases to zero while the system approaches a steady state.

Sustained oscillations

Oscillations that continue indefinitely in time with constant amplitude and frequency.

Guanine nucleotide exchange factor

A protein that catalyses the exchange of GDP for GTP for a GTP-binding protein.

Ordinary differential equation

An equation in which differentiation occurs with respect to only a single independent variable, which is time for chemical kinetic equations.

Analogue signal

A signal the quantity of which (for example, the concentration or activity (amplitude)) changes continuously in time and space, gradually increasing or decreasing.

Digital output

A non-continuous signal that displays discrete levels, for instance zero or one.

Interactome

The complete set of protein–protein interactions in a cell or organism. Interactome is often also used to designate the set of interaction partners of individual proteins.

Partial differential equation

Contains partial derivatives with respect to two or more independent variables, which are time and the spatial coordinates for reaction–diffusion equations.

GTPase-activating protein

A protein that facilitates the hydrolysis of GTP by a GTP-binding protein.

Nanocluster

A transient, nanoscale array of plasma membrane proteins formed by lipid sorting and/or protein–protein interactions.

4-Pi

A laser scanning fluorescence microscope that uses two opposing objectives to improve axial spatial resolution.

Stimulated emission depletion

A fluorescence microscopy technique that uses nonlinear de-excitation of fluorescent dyes to improve the spatial resolution of standard confocal microscopy.

Farnesylation

A post-translational modification in which a farnesyl group (a hydrophobic group of three isoprene units) is conjugated to proteins, such as Ras GTPases, that contain a C-terminal CAAX motif. Farnesylation promotes attachment of the modified proteins to membranes.

Hysteresis

A system that relates current inputs to different steady-state outputs, depending on the previous state of the system; that is, hysteresis provides a memory function to a system.

Heterotrimeric G protein

A protein complex of three proteins (Gα, Gβ and Gγ). Gβ and Gγ form a tight complex, whereas Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

Phosphorylation gradient

A gradual change in the fraction of phosphorylated protein with distance

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Kholodenko, B., Hancock, J. & Kolch, W. Signalling ballet in space and time. Nat Rev Mol Cell Biol 11, 414–426 (2010). https://doi.org/10.1038/nrm2901

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