Analysis of R-Ras signalling pathways

Abstract

Analysis of R-Ras signalling pathways. R-Ras has a high degree of sequence homology to Ras and to other members of the Ras subfamily including Rap, TC21 and ill- Ras. Activated versions of Ras and TC21 are highly transforming in a variety of cell lines and mutated forms of both proteins have been found in human tumours, R-Ras interacts with many of the same proteins as Res and TC21, including c-Raf1, and call induce transformed foci, although this activity is weak compared to Ras and appears to be cell-type specific, Here, we have investigated R-Ras signalling pathways in a variety of cell types, We find that microinjection of activated R-Ras into quiescent fibroblasts stimulates cell cycle progression through G(1) phase and subsequent DNA synthesis. However, unlike Bas, R-Ras does not activate the ERK MAP kinase pathway nor does it activate the JNK or p38/Mpk2 MAP kinase pathways. microinjection of R-Ras into PC12 cells does not induce terminal differentiation, but instead causes extensive cell spreading, consistent with R-Ras having a role in integrin activation. Finally, in a macrophage cell line, R-Ras activates the alphaM beta (2) integrin ria the small GTPase Rapt, leading to phagocytosis of opsonized red blood cells, whereas Ras does not, These results indicate that R-Ras has an important role in the regulation of cell growth and adhesion, but that this is mediated through downstream signals distinct from those used by Ras.