Cell Biology Endocytic Recycling of Ras

Roy et al. bring together two recently described aspects of Ras signaling--one being the distinct localization and biological effects of the different Ras isoforms, H-Ras, N-Ras, and K-Ras, and the other accumulating evidence that activation of the mitogen-activated protein kinase pathway in response to growth factor receptors requires endocytosis. H-Ras, when inactive, is associated with lipid rafts and caveolae, but when activated, the protein is distributed in the disordered plasma membrane. K-Ras is found mainly in the disordered plasma membrane, regardless of its activation state. Roy et al. showed that in PC12 cells, inhibition of endocytosis through expression of a dominant-negative mutant of dynamin inhibited activation of the kinase Raf-1 and differentiation caused by an active mutant of H-Ras. Similar effects of an active K-Ras mutant were not inhibited, however. The phosphatidylinositol 3-kinase inhibitor LY294002 also inhibited activation of Raf-1 by H-Ras but not that by K-Ras. Stimulation of endocytosis and recycling of endocytic vesicles by expression of the small guanosine triphosphatase (GTPase) Rab5 enhanced H-Ras-induced activation of Raf-1. A Rab5 mutant that promotes endocytosis without recycling caused active H-Ras to accumulate in enlarged endosomes and inhibited activation of Raf-1. The authors propose a model in which the differential membrane localization of the Ras isoforms makes them differ in their dependence on endocytosis for full function. H-Ras appears to be recycled to the plasma membrane in endosomes, whereas K-Ras can make it back on its own. Endocytosis may also cycle Raf-1 back to the cytosol after its localization to the cell membrane by activated Ras.

S. Roy, B. Wyse, J. F. Hancock, H-Ras signaling and K-Ras signaling are differentially dependent on endocytosis. Mol. Cell. Biol. 22, 5128-5140 (2002). [Abstract] [Full Text]