Ras

From Academic Kids

This is about a protein. For other meanings see ras (disambiguation).

Ras (in molecular biology) 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.

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 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), which increase the rate of GTP hydrolysis, returning RAS to its GDP-bound form, simultaneously releasing a Pi. 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

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).

Obviously 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 out of control 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 another approaches has been investigated, including targeting the processes responsible for prenylating RAS with the farnesyltransferase inhibitors.

Constitutively active Ras

Constitutively active Ras (RasD) 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

  • Lodish H, Berk H, Zipursky LS, Matsudaira P, Baltimore D. (2000). Molecular Cell Biology, 4th Ed. Ch. 24, Cancer
  • Bos JL. (1989). RAS oncogenes in human cancer: a review. Cancer Res. 49:4682-4689
  • Reuter CWM, Morgan MA, Bergmann L. (2000). Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood. 96(5):1655-1669.es:gen ras
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