Weakness as a strength

JCB • VOLUME 168 • NUMBER 6 • 2005 850 Acyl cycles move Ras cyl groups cycle endlessly on and off Ras to confine the protein to the Golgi and plasma membrane (PM), as shown by Oliver Rocks, Alfred Wittinghofer, Philippe Bastiaens (EMBL, Heidelberg, Germany), and colleagues. These locales are the homes of two Ras isoforms, Nras and Hras, both of which are modified with the acyl group palmitate. Now it is shown that transport to the PM is not a one-way trip for Ras, which cycles back to the Golgi. Deand repalmitoylation drive this cycling. Ras that could not be palmitoylated was found on all membranes. Less stable palmitates, which were more rapidly removed, favored Golgi localization. Other palmitoylated peptides cycled similarly. The results suggest that palmitoylation occurs at the Golgi and temporarily anchors it there. Some of this pool is sent via the exocytic pathway to the PM, where the palmitate group is eventually removed. The low affinity of this depalmitoylated Ras for membranes ensures that it does not accumulate on non-Golgi membranes. “[Ras] is just in sampling mode,” says Bastiaens, “until it encounters the palmitoylation activity.” Activity did not affect Ras cycling, but the authors found that growth factors first activated Ras at the PM. The Golgi pool was activated with kinetics that reflect the speed of Ras retrograde transport. Nras (with its one palmitate) thus beat Hras (which has two) to the Golgi, giving the isoforms distinct signaling capabilities.