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The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins

Nature Cell Biology volume 14, pages 148–158 (2012)Cite this article

A Corrigendum to this article was published on 29 February 2012

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Abstract

We identify a role for the GDI-like solubilizing factor (GSF) PDEδ in modulating signalling through Ras family G proteins by sustaining their dynamic distribution in cellular membranes. We show that the GDI-like pocket of PDEδ binds and solubilizes farnesylated Ras proteins, thereby enhancing their diffusion in the cytoplasm. This mechanism allows more effective trapping of depalmitoylated Ras proteins at the Golgi and polycationic Ras proteins at the plasma membrane to counter the entropic tendency to distribute these proteins over all intracellular membranes. Thus, PDEδ activity augments K/Hras signalling by enriching Ras at the plasma membrane; conversely, PDEδ down-modulation randomizes Ras distributions to all membranes in the cell and suppresses regulated signalling through wild-type Ras and also constitutive oncogenic Ras signalling in cancer cells. Our findings link the activity of PDEδ in determining Ras protein topography to Ras-dependent signalling.

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Figure 1: PDEδ affects the spatial distribution of palmitoylated Ras proteins.
Figure 2: Pharmacological intervention with the Ras acylation cycle affects PDEδ activity.
Figure 3: PDEδ enhances the effective diffusion of farnesylated Ras proteins.
Figure 4: PDEδ solubilizes polybasic-stretch-containing Ras proteins.
Figure 5: PDEδ solubilizes Kras from endomembranes.
Figure 6: PDEδ expression reinstates plasma membrane Ras localization and Ras-mediated signalling.
Figure 7: PDEδ modulates oncogenic Ras signalling.

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Change history

  • 25 January 2012

    In the version of this article initially published online and in print, the y-axis label for the graph in Figure 6b was incorrect. The correct label for the axis is "Normalized Ras-GTP".

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Acknowledgements

We thank D. Vogt and K. Michel for technical support, M. Schmick for assistance with FLAP data analysis, O. Sabet (Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany) for providing mTFP–calreticulin, C. Schmees (Tumor Biology Group, NMI Natural Sciences and Medical Institute, Tübingen University, Reutlingen, Germany) for providing hTERT/SV40 cells and A. Krämer for help in preparing the manuscript.

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Authors and Affiliations

  1. Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany

    Anchal Chandra, Hernán E. Grecco & Philippe I. H. Bastiaens

  2. Department of Structural Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany

    Anchal Chandra, Shehab A. Ismail & Alfred Wittinghofer

  3. Department of Oncology and the Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK

    Venkat Pisupati, David Perera, Liam Cassidy, Ferdinandos Skoulidis & Ashok R. Venkitaraman

  4. Department of Chemical Biology, Max Planck Institute for Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany

    Christian Hedberg

  5. Institute for Molecular Bioscience, University of Queensland, Queensland 4072, Australia

    Michael Hanzal-Bayer

  6. Faculty of Chemistry, Technical University Dortmund, Otto-Hahn-Str.6, 44227 Dortmund, Germany

    Philippe I. H. Bastiaens

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Contributions

A.C. carried out and analysed the experiments, H.E.G. analysed the FLIM data, A.C., V.P., D.P. and L.C. carried out colony-formation assays, F.S. provided mPDAC cells, S.A.I. provided intellectual input, C.H. provided palmostatin-B, M.H-B. provided valuable initial experiments, P.I.H.B. and A.W. conceived the project and P.I.H.B. wrote the paper with A.C. and A.R.V.

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Correspondence to Philippe I. H. Bastiaens.

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Chandra, A., Grecco, H., Pisupati, V. et al. The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins. Nat Cell Biol 14, 148–158 (2012). https://doi.org/10.1038/ncb2394

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