The Ras Proto-oncogene Product

Ras is a central player in signal transduction and is mutated in about a third of all human cancers. Signals through many signalling pathways pass through Ras (Campbell et al., 1998; Vojtek and Der, 1998 for reviews). Ras has four major isoforms, N-, H-, Ka- and Kb-, each differing mainly in the posttranslationally modified C-terminus of Ras. The distribution of the four isoforms differs between different types of cancer, suggesting that understanding the extreme C-terminus of Ras is of fundamental importance in understanding the human cancer process.

Unstimulated Ras has a GDP nucleotide bound, which is exchanged for a GTP on stimulation. Replacement of GDP with GTP is stimulated by SOS1 and the subsequent deactivating hydrolysis of GTP to GDP is catalysed by RasGAP's (Geyer and Wittinghoffer,1997). Ras is also posttranslationally modified, with the addition of a farnesyl lipid group to the C-terminus, catalysed by Farnesyl Tranferase (FTase) and a palmitoyl group just before the C-terminus is also added to three of the four isoforms (Kato et al., 1992). One of the more exciting developments in Ras biology in the late 1990's has been the development of FTase inhibitors, which prevent farnesylation of Ras and so prevent Ras activity and selectively kill Ras-transformed cancer cells. However a great debate is now underway on whether Ras is actually the target of FTase inhibitors or it is other farnesylated proteins that are important in killing these transformed cells (Lebowitz et al., 1998; Zohn et al., 1998). This debate has not prevented the development of clinical trials for FTase inhibitors however.

RasGTP has several downstream targets, including PI3K, Raf, RalGDS, MEKK and AF6, which suggests Ras is involved in many, many cellular functions (Campbell et al., 1998; Vojtek and Der, 1998). Perhaps the best characterised downstream effector of Ras is Raf which leads to the MAP kinase pathway. Stimulation of Raf is another story entirely (see the Raf page).

Kindly contributed by: Rob McPherson

References

• Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ Oncogene 1998 Sep 17;17(11 Reviews):1395-413 Increasing complexity of Ras signaling.
• Geyer M, Wittinghofer A Curr Opin Struct Biol 1997 Dec;7(6):786-792 GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins.
• Kato K, Der CJ, Buss JE Semin Cancer Biol 1992 Aug;3(4):179-188 Prenoids and palmitate: lipids that control the biological activity of Ras proteins.
• Lebowitz PF, Prendergast GC Oncogene 1998 Sep 17;17(11 Reviews):1439-1445 Non-Ras targets of farnesyltransferase inhibitors: focus on Rho.
• Vojtek AB, Der CJ J Biol Chem 1998 Aug 7;273(32):19925-8 Increasing complexity of the Ras signaling pathway.
• Zohn IM, Campbell SL, Khosravi-Far R, Rossman KL, Der CJ Oncogene 1998 Sep 17;17(11 Reviews):1415-38 Rho family proteins and Ras transformation: the RHOad less traveled gets congested.