RAS family
Franz Watzinger, Thomas Lion
March 1999
(Children Cancer Reserch Institute, St. Anna Children's Hospital, A-1090 Vienna, AUSTRIA)
DNA/RNA
The establishment of an in vitro assay to screen for active transformation ofmouse NIH 3T3 fibroblasts has revealed transforming genes identified as humanhomologs of Harvey or Kirsten murine sarcoma virus oncogenes (v-Ha-ras, or v-Ki-ras,respectively). Thereupon, an additional transforming gene was found in human neuroblastomaand fibrosarcoma cell lines that has been identified as the third functional memberof the ras gene family. This gene have been termed N-ras. Thus, the human rasfamily consists of three proto-oncogenes, c-Harvey(H)-ras, c-Kirsten (K)-ras, and N-ras,no c-prefix was added because no viral counterpart was found. Additionally, geneswere found in the genome of human and other mammalian species that display highhomology to the functional ras genes but lack intervening sequences (introns).These genes were identified as processed and inactivated pseudogenes. Functionalras genes differ greatly in length due to large differences in the size of theirintrons ranging from about 6kb to 50kb, but they each have 4 coding exons. Thehuman K-ras gene contain an alternative fourth coding exon. Alternative RNA splicingspecifies either of two isomorphic proteins differing by 25 amino acid residuesat their carboxy-terminus. Ras genes are expressed in all tissues, have a promotorregion with multiple GC boxes, but lack a TATA- or CCAT-box; features resemblingthe promotors of housekeeping genes (Lowndes et al., 1999).
A comparison of human H-, K-, and N-ras nucleotide sequences with the correspondingregions in other mammalian species reveals a remarkable sequence similarity (Watzingeret al., 1998). All differences are synonymous changes with no effect on the aminoacid sequence of RAS proteins, indicating a strong evolutionary pressure on theamino acid sequence of these genes.
The ras oncogenes in various human tumors harbor point mutations that confer transformingactivity. Mutations leading to an amino acid substitution at the positions 12,13, and 61 are the most common in naturally occurring (i.e. non-experimental)(Kiaris and Spandidos, 1999) neoplasms and experimentally induced animal tumors(Mangues and Pellicer, 1992; Stanley, 1995) (see following sections).
In addition to the most frequent mechanism of point-mutational activation, overexpressionof non-mutated ras genes can also convert normal ras genes into oncogenes. Theincreased amount of the corresponding mRNA derives either from high transcriptionalactivity of heterologous promotors and enhancers (Chakraborty et al., 1991) orresults from amplified ras genes located either intrachromosomally as homogeneouslystaining regions or extrachromosomally as double minute chromosomes (Nishimuraand Sekiya, 1987).
Functional aspects of RAS proteins
Mammalian ras genes code for closely related, small proteins of 189 amino acids witha molecular weight of 21,000 Daltons (p21). When the alternative exon of H- or K-rasis used, proteins of 170 or 188 amino acids are synthesized. The molecular weightof the H-ras protein variant is 19,000 Daltons and that of the K-ras variant is notdistinguishablefrom the normal RAS proteins.
RAS proteins are localized in the inner plasma membrane, bind GDP and GTP andpossess an intrinsic GTPase activity, implicated in the regulation of their activity.Because of the functional resemblance to G-Proteins, p21RAS have been hypothesizedto be also involved in different types of ligand-mediated signal transductionpathways. Later, RAS proteins were shown to influence proliferation, differentiation,transformation, and apoptosis by relaying mitogenic and growth signals into thecytoplasm and the nucleolus (Khosravi Far and Der, 1994). In a normal cell mostof the RAS molecules are present in an inactive GDP-bound conformation. An extracellularstimulus initiates the release of GDP and the subsequent binding of GTP. Thisconformational change enables the interaction with the putative effector moleculesand permits the transmission of signals. Finally, the active GTP-bound state isturned off by hydrolysis of GTP to GDP and inorganic phosphate.
The intrinsic GTPase activity is rather weak, not sufficiently effective for signaltransduction pathways where rapid inactivation is required. In order to acceleratethis low rate of hydrolysis (which is about 10-2 min-1) and to enable a transientburst of signalling activity, regulatory proteins like GAPs (GTPase activatingproteins) (Ahmadian et al., 1996) or NF-1(Neurofibromatosis Type 1) protein (McCormick, 1995), bind to the GTP-containingconformation and stimulate the GTPase activity more than 100-fold. The decreasinglevel of RAS-GTP, and hence, increasing level of RAS-GDP complexes result in aloss of the biological activity of RAS (see Fig. 1). In a normal cell, GAPs helpto keep most of p21RAS in an inactive GDP-bound state. The finding that overexpressionof non-mutated ras genes can also transform cells supports the idea that the abundanceof GAPs is limited. Overexpression of p21RAS could lead to saturation of the regulatoryproteins, resulting in a constitutive, deregulated activation of RAS proteinsand oncogenic transformation.
Another group of regulatory proteins involved in stimulating the transition ofRAS proteins from the inactive- to the active GTP-bound state are designated GuanineNucleotide Exchange Factors (GEFs) or RAS-GRFs (guanine nucleotide releasing factors)(Satoh and Kaziro, 1992). Normally, the release of GDP is regulated by the intracellularconcentration of GTP. An increase in the GTP concentration leads to an enhanceddissociation of GDP. GEFs catalyze the dissociation of GDP (see Fig.1). A ligand-freeRAS protein immediately binds GTP, because it is 10-fold more abundant in thecytosol than GDP.
Figure 1
Figure 1 Mechanism of RAS regulation
The activity of RAS proteins is regulated by a cycle of guanine nucleotide bindingand hydrolysis. In the active state p21 is bound to GTP, in the inactive to GDP.GEF (Guanine Nucleotide Exchange Factor) promotes dissociation of GDP and acts asa positive regulator; GAP (GTPase activating protein) promotes hydrolysis of GTPand acts asa negative regulator. Pi, inorganic phosphate.
Structure of RAS proteins
The alignment of their primary amino acid sequence clearly indicates the presenceof four domains within the RAS molecules. The first domain includes 85 amino acidsat the N-terminus which are found to be identical in H-, K-, and N-ras, demonstratinga high degree of conservation. The following 80 amino acids form a second domain, showingless conservation (70-80%) within the RAS proteins. The third domain spans the restof the molecule, except for the last four amino acids, and represents a hypervariableregion. The highly conserved carboxy-terminal motif CAAX (where C stands for cysteine,A for any aliphatic residue, and X for any uncharged amino acid) is the result ofposttranslational modifications and forms the last domain.
For more accurate identification of biologically relevant regions of p21RAS and forthe interpretation of activating mutations, X-crystallographic analysis of GDP- andGTP-bound RAS molecules and in vitro mutagenesis studies with mutated or truncatedRAS proteins were performed. As a result of these studies, the catalytic domain was identifiedbetween residues 1 to 171, including the region involved in guanine nucleotide bindingwhere residues 10-16 and 56-59 interact with b- and c-phosphate, and residues 116-119 and 152-165 interact with the guanine base., The so called core effector region(located between residues 32-40), represents an essential element for all interactionswith putative downstream effectors and the GAPs. A region encompassing the last four amino acids at the C-terminus (residues 186-189), was shown to be essential forthe attachment of p21RAS to the plasma membrane.
Comparison of the crystal structure of RAS-GTP (as indicated in Fig.2) and RAS-GDPcomplexes revealed that switching between the active and the inactive state isassociated with a conformational change of two regions, designated as switch I(residues 30-38), overlapping with the core effector region, and switch II (60-76).Binding of the neutralizing antibody Y13-259 to residues 63-73, inhibits the GTP-GDPchange, indicating that this conformational change is necessary for the transitionof RAS from the GDP- to the GTP-bound state and vice versa (Milburn et al., 1990;Scheffzek et al., 1997).
Figure 2
Figure 2 Topological structure of p21
The polypeptide chain of RAS p21 consists of six b-strands and five a-helices. Loop 1, alias phosphate-binding (P-) loop (residues 10 to 16), switch regions I (30 to 37), including loop 2 with adjacent residues, and II (60 to 67), including loop 4 and a-helix 2, represent the active center of the molecule and are involved in the binding interaction between p21RAS and GTP. N stands for the amino terminal, C for the carboxy terminal end.
(modified figure reprinted from Seminars in Cancer Biology vol 3, (4), F Wittinghofer, Tree-dimentional structure of p21H-ras and its implications, p189-198, 1992, by permission of the publisher Academic Press).
Activating point mutations have been localized in codons 12, 13, 59, 61, 63, 116, 117, 119, and 146 (Barbacid, 1990). All of these alterations occur at or near the guanine nucleotide binding sites. The effects of point mutations are either reduced GTPase activity (if amino acids 12, 13, 59, 61, 63 are involved), so that oncogenic RAS mutants are locked in the active GTP-bound state, or decreased nucleotide affinity, and hence, increased exchange of bound GDP for cytosolic GTP (if amino acids 116, 117, 119 or 146 are affected). The inefficient deactivation of the active GTP-bound RAS proteins is intensified by the inability of GAPs to stimulate the conversion to the inactive, GDP-bound state. All point mutations cause an accumulation of activated RAS-GTP complexes, leading to continuous signal transduction by facilitating accumulation of constitutively active, GTP-bound RAS protein, and thus contributing to a malignant cell phenotype.
Incidence of ras mutations
(see also the appendix)Activating ras mutations can be found in human malignancies with an overall frequencyof 15-20%. A high incidence of ras gene mutations has been reported in malignanttumors of the pancreas (80-90%, K-ras) (Ballas et al., 1988; Smit et al., 1988),in colorectal carcinomas (30-60%, K-ras)(Breivik J et al., 1994; Spandidos et al., 1996), in non-melanoma skin cancer(30-50%, H-ras) (Barbacid, 1990; Rodenhuis, 1992), in hematopoietic neoplasiaof myeloid origin (18-30%, K-and N-ras) (Breivik et al., 1994; Nakagawa et al.,1992; Neubauer et al., 1994; Satoh and Kaziro, 1992), and in seminoma(25-40%, K-ras) (Mulder et al., 1989; Ridanpaa et al., 1993). In other tumors,a mutant ras gene is found at a lower frequency: for example, in breastcarcinoma (0-12%, K-ras) (Rochlitz et al., 1989; Spandidos, 1987), glioblastomaand neuroblastoma (0-10%, K- and N-ras)(Ballas et al., 1988; Brustle et al., 1996; Ireland, 1989).
Appendix : RAS mutations in various cancers and bibliography
H-RAS mutations
| Tumor | Frequency (%) | Reference |
|---|---|---|
| Stomach | 0-40 | (Deng et al., 1991; Kim et al., 1997; Miki et al., 1991; Nanus et al., 1990; Victor et al., 1990) |
| Urinary Bladder | 0-65 | (Hong et al., 1996; Malone et al., 1985; Olderoy et al., 1998; Saito et al., 1997; Visvanathan et al., 1988) |
| Prostate | 0-10 | (Carter et al., 1990; Gumerlock et al., 1991; Konishi et al., 1997; Shiraishi et al., 1998) |
| Skin | 0-45 | (Campbell et al., 1993; Tormanen and Pfeifer, 1992) |
| Thyroid | 0-60 | (Bouras et al., 1998; Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine et al., 1989; Suarez et al., 1988) |
| Breast | 0-10 | (Kraus et al., 1984; Spandidos, 1987) |
| Head and neck | 0-30 | (Clark et al., 1993; Kiaris et al., 1995; Rumsby et al., 1990; Saranath et al., 1991) |
| Endometrium | 5 | (Varras et al., 1996) |
K-RAS mutations
| Tumor | Frequency (%) | Reference |
|---|---|---|
| Pancreas | 80-90 | (Almoguera et al., 1988; Smit et al., 1988; Watanabe et al., 1996) |
| Colon and rectum | 25-60 | (Boughdady et al., 1992; Breivik et al., 1994; Burmer et al., 1991; Halter et al., 1992; Kojima et al., 1997; Oudejans et al., 1991; Spandidos et al., 1996; Ward et al., 1998; Yamagata et al., 1994) |
| Lung | 25-60 | (Husgafvel-Pursiainen et al., 1992; Rodenhuis and Slebos, 1992; Rodenhuis et al., 1997; Sagawa et al., 1998; Suzuki et al., 1990) |
| Prostate | 0-25 | (Capella et al., 1991; Carter et al., 1990; Gumerlock et al., 1991; Konishi et al., 1992; Konishi et al., 1997; Shiraishi et al., 1998) |
| Skin | 0-25 | (Albino et al., 1991; Shukla et al., 1989) |
| Thyroid | 0-60 | (Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine et al., 1989; Suarez et al., 1988) |
| Liver | 10-25 | (Challen et al., 1992; Marion et al., 1991; Tada et al., 1990; Tada et al., 1992) |
| Ovary | 0-50 | (Enomoto et al., 1991; Ichikawa et al., 1994; Teneriello et al., 1993) |
| Endometrium | 10-40 | (Duggan et al., 1994; Enomoto et al., 1991; Ignar-Trowbridge et al., 1992; Mizuuchi et al., 1992; Sasaki et al., 1993; Semczuk et al., 1997; Varras et al., 1996) |
| Kidney | 0-50 | (Nagata et al., 1990; Skalkeas et al., 1991) |
| Brain | 0-15 | (Ballas et al., 1988; Ballas et al., 1988; Brustle et al., 1996; Ireland, 1989; Maltzman et al., 1997) |
| Testis (Seminoma) | 10-45 | (Moul et al., 1992; Mulder et al., 1989; Ridanpaa et al., 1993) |
| Leukemia (ANLL, MDS) | 5-15 | (Nakagawa et al., 1992; Neubauer et al., 1994; Padua et al., 1998; Sheng et al., 1997) |
| Urinary Bladder | 5 | (Olderoy et al., 1998) |
| Head and neck | 10 | (Rathcke et al., 1996; Rumsby et al., 1990) |
| Breast | 10 | (Dawson et al., 1996) |
N-RAS mutations
| Tumor | Frequency (%) | Reference |
|---|---|---|
| Leukemia ANLL, MDS | 20-40 | (De Melo et al., 1997; Nakagawa et al., 1992; Neubauer et al., 1994; Padua et al., 1998; de Souza Fernandez et al., 1998; Syvanen et al., 1992) |
| Leukemia CML,ALL | 0-10 | (Watzinger et al., 1994; Yokota et al., 1998) |
| Brain | 0-15 | (Ballas et al., 1988; Bos, 1988; Brustle et al., 1996; Ireland, 1989; Maltzman et al., 1997) |
| Skin | 0-20 | (Albino et al., 1984; Mooy et al., 1991; Soparker et al., 1993; van't Veer et al., 1989) |
| Thyroid | 0-60 | (Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine et al., 1989; Suarez et al., 1988) |
| Testis | 0-40 | (Moul et al., 1992; Mulder et al., 1989; Ridanpaa et al., 1993) |
| Stomach | (gastric tumors) 5 | (Kim et al., 1997) |
| Liver | 0-15 | (Challen et al., 1992; Tada et al., 1990; Tada et al., 1992) |
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| Written | 1999-03 | Franz Watzinger, Thomas Lion |
| Cancer Research Institute (CCRI), Kinderspitalgasse 6, A-1090 Vienna, Austria |
| Citation |
| This paper should be referenced as such : |
| Watzinger, F ; Lion, T |
| RAS family |
| Atlas Genet Cytogenet Oncol Haematol. 1999;3(2):116-123. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Deep/RasID20002.htm |
Citation
Atlas of Genetics and Cytogenetics in Oncology and Haematology
RAS family
Online version: http://atlasgeneticsoncology.org/deep-insight/20002/ras-family
