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Ras is a family of genes encoding small GTPases that are involved in cellular signal transduction. Activation of Ras signalling causes cell growth, differentiation and survival. Ras is the prototypical member of the Ras superfamily of proteins which are all related in structure and regulate diverse cell behaviours. Since Ras communicates signals from outside the cell to the nucleus, mutations in ras genes can permanently activate it and cause inappropriate transmission inside the cell even in the absence of extracellular signals. Because these signals result in cell growth and division, dysregulated Ras signaling can ultimately lead to oncogenesis and cancer.[1] Activating mutations in Ras are found in 20-25% of all human tumors and up to 90% in specific tumor types.[2]
[edit] HistoryThe ras genes were first identified as the transforming oncogenes,[3] responsible for the cancer-causing activities of the Harvey (the HRAS oncogene) and Kirsten (KRAS) sarcoma viruses, by Edward M. Scolnick and colleagues at the National Institutes of Health (NIH).[4] These viruses were discovered originally in rats during the 1960s by Jennifer Harvey[5] and Werner Kirsten,[6] respectively, hence the name Rat sarcoma. In 1982, activated and transforming human RAS genes were discovered in human cancer cells by Geoffrey M. Cooper at Harvard,[7] Mariano Barbacid and Stuart A. Aaronson at the NIH[8] and by Robert Weinberg of MIT.[9] Subsequent studies identified a third human RAS gene, designated NRAS, for its initial identification in human neuroblastoma cells. The three human RAS genes encode highly related 188 to 189 amino acid proteins, designated H-Ras, N-Ras and K-Ras4A and K-Ras4B (the two K-Ras proteins arise from alternative gene splicing). [edit] The Ras superfamilyThere are more than a hundred proteins in the Ras superfamily.[10] Based on structure, sequence and function, the Ras superfamily is divided into eight main families, each of which is further divided into subfamilies: Ras, Rho, Rab, Rap, Arf, Ran, Rheb, Rad and Rit. Miro is a recent contributor to the superfamily. Each subfamily shares the common core G domain, which provides essential GTPase and nucleotide exchange activity. The surrounding sequence helps determine the functional specificity of the small GTPase, for example the 'Insert Loop', common to the Rho subfamily, specifically contributes to binding to effector proteins such as IQGAP and WASP. The Ras family is generally responsible for cell proliferation, Rho for cell morphology, nuclear transport for Ran and vesicle transport for Rab and Arf:[11] The following is a list of human proteins belong to the Ras superfamily:[10] Unclassified: [edit] Structure
Ras contains 6 beta sheets and 5 alpha helices:[12]
The G domain contains five G motifs that bind GDP/GTP directly
and two switches which are the main parts of the protein that move during activation
Ras also binds a magnesium ion which helps to coordinate nucleotide binding. [edit] Function Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, proliferation, differentiation, 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 activates several pathways, of which the mitogen-activated protein (MAP) kinase cascade has been well-studied. This cascade transmits signals downstream and results in the transcription of genes involved in cell growth and division.[13] There is a separate AKT pathway that inhibits apoptosis. [edit] Activation and deactivationRas is a G protein, or a guanosine-nucleotide-binding protein. Specifically, it is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases). G proteins function as binary signaling switches with "on" and "off" states. In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP), while in the "on" state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP. This extra phosphate holds the two switch regions in a "loaded-spring" configuration (specifically the Thr-35 and Gly-60). When released, the switch regions relax which causes a conformational change into the activated state. Hence, activation and deactivation of Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive GDP-bound forms. The process of exchanging the bound nucleotide is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). As per its classification, Ras has an intrinsic GTPase activity, which means that the protein on its own will hydrolyze a bound GTP molecule into GDP. However this process is too slow for efficient function, and hence the GAP for Ras, RasGAP may bind to and stabilize the catalytic machinery of Ras, supplying additional catalytic residues ("arginine finger") such that a water molecule is optimally positioned for nucleophilic attack on the gamma-phosphate of GTP. An inorganic phosphate is released and the Ras molecule is now bound to a GDP. Thus, GAPs regulate Ras inactivation. GEFs catalyze a "push and pull" reaction which releases GDP from Ras. They insert close to the P-loop and magnesium cation binding site and inhibit the interaction of these with the gamma phosphate anion. Acidic (negative) residues in switch II "pull" a lysine in the P-loop away from the GDP which "pushes" switch I away from the guanine. The contacts holding GDP in place are broken and it is released into the cytoplasm. Because intracellular GTP is abundant relative to GDP (approximately 10 fold more[citation needed]) GTP predominantly re-enters the nucleotide binding pocket of Ras and reloads the spring. Thus GEFs facilitate Ras activation.[12] Well known GEFs include Son of Sevenless (Sos) and cdc25 which include the RasGEF domain. The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity. In the GTP-bound conformation, Ras has high affinity for numerous effectors which allow it to carry out its functions. These include PI3K. Other small GTPases may bind adaptors such as arfaptin or second messenger systems such as adenylyl cyclase. The Ras binding domain is found in many effectors and invariably binds to one of the switch regions, because these change conformation between the active and inactive forms. However, they may also bind to the rest of the protein surface. [edit] Membrane attachmentRas 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.[14] The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol and then inserted into the membrane of the endoplasmatic reticulum. The Tripeptide (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease, the new C-terminus is then methylated by a methyltransferase. The so processed Ras is now transported to the plasma membrane. Most Ras forms are now further palmitoylated, while K-Ras with its long positively charged stretch interacts electrostaticly with the membrane. [edit] Ras in cancerMutations 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.[15] it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain cancer types. Ras point mutations are the single most common abnormality of human proto-oncogenes.[16] Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib) exhibits profound anti-oncogenic effects in many cancer cell lines.[17][18] [edit] Inappropriate activationInappropriate activation of the gene has been shown to play a key role in signal transduction, proliferation and malignant transformation.[13] 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.[14] [edit] Constitutively active RasConstitutively 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 G12 in the P-loop and the catalytic residue Q61.
See also "dominant negative" mutants such as S17N and D119N. [edit] References
[edit] External links
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