Mechanisms of Ras protein targeting in mammalian cells

Many physiological and oncogenic activities of the 'classical' Ras proteins (H-Ras, N-Ras and K-Ras4A and -4B) require their correct localization to the plasma membrane. Nascent Ras proteins, however, initially associate with endomembranes (the ER and in some cases the Golgi) to complete the processing of their farnesylated carboxyl-termini before they are delivered to the plasma membrane. Recent work has revealed the outlines of the intracellular pathways by which Ras proteins reach their ultimate plasma membrane destination and has indicated that these pathways differ for different Ras species. Other studies have demonstrated that mature Ras proteins can transfer between the plasma membrane and intracellular membranes, and that Ras proteins may in some cases signal from intracellular compartments. This review will describe recent progress and still-unresolved questions in these areas.