TY - JOUR
T1 - The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins
AU - Chandra, Anchal
AU - Grecco, Hernãin E.
AU - Pisupati, Venkat
AU - Perera, David
AU - Cassidy, Liam
AU - Skoulidis, Ferdinandos
AU - Ismail, Shehab A.
AU - Hedberg, Christian
AU - Hanzal-Bayer, Michael
AU - Venkitaraman, Ashok R.
AU - Wittinghofer, Alfred
AU - Bastiaens, Philippe I.H.
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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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U2 - 10.1038/ncb2394
DO - 10.1038/ncb2394
M3 - Article
C2 - 22179043
AN - SCOPUS:84856492497
SN - 1465-7392
VL - 14
SP - 148
EP - 158
JO - Nature cell biology
JF - Nature cell biology
IS - 2
ER -