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. Molecular biology is the study of biology at a molecular level. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... In biology, signal transduction is any process by which a cell converts one kind of signal or stimulus into another. ... A cell undergoing apoptosis. ... Metastasis (Greek: change of the state) is the spread of cancer from its primary site to other places in the body. ... RhoA is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. ... Rab is a member of the Ras superfamily of GTPases. ...

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). G-proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. ... In biology, small GTPases are small (20-25 KDa) proteins that bind to guanosine triphosphate GTP. This family of proteins are homologous to Ras GTPases and also called the Ras superfamily GTPases. ... Guanosine triphosphate (GTP) is also known as guanosine-5-triphosphate. ... RasGAP (Ras GTPase activating protein) is a 120-kDa cytosolic protein that provides two principal activities: Inactivation of Ras from its active GTP-bound form to its unactive GDP-bound form by enhancing the endogenous GTPase activity of Ras, via its C-terminal GAP domain Mitogenic signal transmission towards downstream... Illustration of a lipid bilayer A cell membrane, plasma membrane or plasmalemma is a selectively permeable lipid bilayer coated by proteins which comprises the outer layer of a cell. ... Prenylation or isoprenylation is the addition of hydrophobic molecules to a protein to facilitate its attachment to the cell membrane. ... A cell in early anaphase Mitosis is the process by which a cell separates its duplicated genome into two identical halves. ... In cell biology, mitogen-activated protein kinases (MAPKs) (EC 2. ...

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). An oncogene is a gene that can cause a cell to develop into a tumor cell, possibly resulting in cancer. ...

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). An oncogene is a modified gene that increases the malignancy of a tumor cell. ... A tumor suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. ... Neurofibromatosis type I (NF-1), also known as von Recklinghausen syndrome, comprises, along with neurofibromatosis type II (a. ... Neurofibromatosis is an autosomal dominant genetic disorder. ...

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, 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. Prenylation or isoprenylation is the addition of hydrophobic molecules to a protein to facilitate its attachment to the cell membrane. ... The farnesyltransferase inhibitors are a class of experimental cancer drugs that target the Ras protein, which is commonly abnormally active in cancer. ...

Constitutively active Ras

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.

A usual question about RAS is as follows: The glycine at position 12 of ras is important. How does a mutation at this position, that changes it to any other amino acid except proline, cause mutant cells to become cancerous?

a. mutations at this position disrupt the ability of ras to associate with a GEF, thereby rendering it hyperactive b. this amino acid is involved in the catalytic cleft of the ras GTPase c. this mutation affects the ability of ras to hydrolyze GDP to GTP d. this residue is critical for an interaction with a protein that helps ras convert GTP to GDP. e. none of the above

The answer is of course d.this residue is critical for an interaction with a protein that helps ras convert GTP to GDP.

References

• Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000). “Chapter 24, Cancer”, Molecular cell biology, 4th, San Francisco: W.H. Freeman. ISBN 0-7167-3706-X.
• Bos J (1989). "ras oncogenes in human cancer: a review.". Cancer Res 49 (17): 4682-9. PMID 2547513.
• Reuter C, Morgan M, Bergmann L (2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?". Blood 96 (5): 1655-69. PMID 10961860.

Further reading

• [1] [2] "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)."