In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. Proteins in the Ras family are very important molecular switches for a wide variety of signal pathways that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis, and cell migration. Ras and ras related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis. The Ras superfamily includes the Ras, Rho, and Rab families.

RAS is a G protein (specifically a small GTPase): a regulatory GTP hydrolase that cycles between two conformations – an activated or inactivated form, respectively RAS-GTP and RAS-GDP. It is activated by guanine exchange factors (GEFs, eg. CDC25, SOS1 and SOS2, SDC25 in yeast), which are themselves activated by mitogenic signals and through feedback from Ras itself. It is inactivated by GTPase-activating proteins (GAPs, the most frequently cited one being RasGAP), which increase the rate of GTP hydrolysis, returning RAS to its GDP-bound form, simultaneously releasing an inorganic phosphate. RAS is attached to the cell membrane by prenylation, and in health is a key component in many pathways which couple growth factor receptors to downstream mitogenic effectors involved in cell proliferation or differentiation (Reuter et al., 2000). RAS activates a number of pathways but an especially important one seems to be the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins (Lodish et al., 2000).

RAS in cancer

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Mutations in the RAS family of proto-oncogenes (comprising H-RAS, N-RAS and K-RAS) are very common, being found in 20% to 30% of all human tumours (Bos JL, 1989).

Inappropriate activation of the gene has been shown to play a key role in signal transduction, proliferation and malignant transformation (Lodish et al., 2000). Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of RAS, so if they are constitutively activated their signals will transduce through RAS. The tumour suppressor gene NF1 encodes a RAS-GAP – its mutation in neurofibromatosis will mean that RAS is less likely to be inactivated. RAS can also be amplified, although this only occurs occasionally in tumours. Finally, RAS oncogenes can be activated by point mutations so that its GTPase reaction can no longer be stimulated by GAP – this increases the half life of active RAS-GTP mutants (Reuter et al., 2000).

Because it is central in so many pathways, and prominent in so many tumours it would be extremely useful if a drug was found which could reintroduce regulation in to the RAS system, or kill cells with uncontrolled RAS pathways. Ideally a drug targeting RAS would be able to distinguish between its oncogene and the normal homolog - simply targeting all cells with RAS would also affect normal cells as well, producing toxic side effects. However the differences between these molecules is very slight (resulting from single amino acid changes) and this might prove a very difficult task. Instead, other approaches have been investigated, including targeting the processes responsible for prenylating RAS with the farnesyltransferase inhibitors.

Constitutively active Ras

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Constitutively active Ras (Ras^D) is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state. The most common mutations are found at residue 12 and residue 61. The glycine to valine mutation at residue 12 renders Ras insensitive to inactivation by GAP and thus stuck in the "on state". Ras requires a GAP for inactivation as it is a relatively poor catalyst on its own, as opposed to other G-domain-containing proteins such as the alpha subunit of heterotrimeric G proteins. Residue 61 is responsible for stabilizing the transition state for GTP hydrolysis. Because enzyme catalysis in general is achieved by lowering the energy barrier between substrate and product, mutation of Q61 necessarily reduces the rate of intrinsic Ras GTP hydrolysis to physiologically meaningless levels.

See also "dominant negative" mutants such as S17N and D119N.

References

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Further reading

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• ^* "Researchers at the University of Calgary originally created a stir with their reovirus treatment announcement back in 1998. Reovirus treatment of cancer is interesting because it appears to specifically target and kill cancer cells while normal cells are unharmed. The virus' selectivity seems to be due to the Ras signaling pathway in cancerous cells. The Ras pathway inhibits activity of an RNA-activated protein kinase (RPK) and allows the virus to replicate in cancer cells (elevated activity of RPK in "normal" cells inhibits reovirus replication)."

G proteins | gen ras