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

• Published in: Nature cell biology Vol. 14; no. 2; pp. 148 - 158
• Main Authors: Chandra, Anchal, Grecco, Hernán E., Pisupati, Venkat, Perera, David, Cassidy, Liam, Skoulidis, Ferdinandos, Ismail, Shehab A., Hedberg, Christian, Hanzal-Bayer, Michael, Venkitaraman, Ashok R., Wittinghofer, Alfred, Bastiaens, Philippe I. H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2012; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animals; Biological transport; Biomedical and Life Sciences; Blotting, Western; Cancer Research; Cell Biology; Cell Line; Cell Membrane - metabolism; Cellular signal transduction; Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism; Developmental Biology; Fluorescence Recovery After Photobleaching; Fluorescence Resonance Energy Transfer; G proteins; Genetic aspects; Golgi Apparatus - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Guanine Nucleotide Dissociation Inhibitors - genetics; Guanine Nucleotide Dissociation Inhibitors - metabolism; Hep G2 Cells; Humans; Intracellular Membranes - metabolism; Life Sciences; Lipoylation; Microscopy, Confocal; Molecular Sequence Data; Physiological aspects; Prenylation; Protein Binding; ras Proteins - genetics; ras Proteins - metabolism; RNA Interference; Signal Transduction; Stem Cells; United States
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb2394

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. Bastiaens and colleagues find that PDEδ can solubilize Ras family small GTPases, resulting in their release from cellular membranes. This concentrates Ras proteins at specific subcellular locations, which promotes their eventual association with the plasma membrane and potentiates Ras-mediated signal transduction.