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Plasma membrane nanoswitches generate high-fidelity Ras signal transduction

Nature Cell Biology volume 9, pages 905–914 (2007)Cite this article

Abstract

Ras proteins occupy dynamic plasma membrane nanodomains called nanoclusters. The significance of this spatial organization is unknown. Here we show, using in silico and in vivo analyses of mitogen-activated protein (MAP) kinase signalling, that Ras nanoclusters operate as sensitive switches, converting graded ligand inputs into fixed outputs of activated extracellular signal-regulated kinase (ERK). By generating Ras nanoclusters in direct proportion to ligand input, cells build an analogue–digital–analogue circuit relay that transmits a signal across the plasma membrane with high fidelity. Signal transmission is completely dependent on Ras spatial organization and fails if nanoclustering is abrogated. A requirement for high-fidelity signalling may explain the non-random distribution of other plasma membrane signalling complexes.

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Figure 1: Raf is recruited to K-ras nanoclusters on the plasma membrane.
Figure 2: Spatial model of MAPK activation in Ras signalling nanoclusters.
Figure 3: Ras nanocluster formation.
Figure 4: Comparison of switch-like and graded MAPK module outputs on ERKpp generation.
Figure 5: Ras nanoclustering is essential for signal transduction.
Figure 6: Ras nanoswitches are essential for high-fidelity signal transduction.

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Acknowledgements

This work was supported by grants from the Queensland Cancer Fund and The National Health and Medical Research Council, Australia. The Institute for Molecular Bioscience is a Special Research Centre of the Australian Research Council.

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Author notes

  1. Angus Harding

    Present address: Current address: Department of Pathology and Immunology, Washington University, St Louis, Missouri 63015, USA.,

  2. Tianhai Tian and Angus Harding: These authors contributed equally to the paper.

Authors and Affiliations

  1. Institute for Molecular Bioscience, University of Queensland, Brisbane, 4072, Australia

    Tianhai Tian, Angus Harding, Kerry Inder, Sarah Plowman, Robert G. Parton & John F. Hancock

  2. Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, 4072, Australia

    Robert G. Parton

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Correspondence to John F. Hancock.

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Supplementary Figures 1, 2, 3, 4, and 5 and Supplementary Tables 1 2 and 3 (PDF 1570 kb)

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Tian, T., Harding, A., Inder, K. et al. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nat Cell Biol 9, 905–914 (2007). https://doi.org/10.1038/ncb1615

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