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Deep Insight Section
RAS family
Franz Watzinger, Thomas Lion
Childrenïs Cancer Research Institute, Kinderspitalgasse 6, A-1090 Vienna, Austria (FW, TL)
Published in Atlas Database: March 1999
Online updated version : http://AtlasGeneticsOncology.org/Deep/Ras.html
DOI: 10.4267/2042/37525
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology
sequence of RAS proteins, indicating a strong
evolutionary pressure on the amino acid sequence of
these genes.
The ras oncogenes in various human tumors harbor
point mutations that confer transforming activity.
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 pointmutational activation, overexpression of non-mutated
ras genes can also convert normal ras genes into
oncogenes. The increased amount of the corresponding
mRNA derives either from high transcriptional activity
of heterologous promotors and enhancers (Chakraborty
et al., 1991) or results from amplified ras genes located
either intrachromosomally as homogeneously staining
regions or extrachromosomally as double minute
chromosomes (Nishimura and Sekiya, 1987).
DNA/RNA
The establishment of an in vitro assay to screen for
active transformation of mouse NIH 3T3 fibroblasts
has revealed transforming genes identified as human
homologs 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 neuroblastoma and fibrosarcoma cell lines
that has been identified as the third functional member
of the ras gene family. This gene have been termed Nras. Thus, the human ras family consists of three protooncogenes, c-Harvey (H)-ras, c-Kirsten (K)-ras, and Nras, no c-prefix was added because no viral counterpart
was found. Additionally, genes were found in the
genome of human and other mammalian species that
display high homology to the functional ras genes but
lack intervening sequences (introns). These genes were
identified as processed and inactivated pseudogenes.
Functional ras genes differ greatly in length due to
large differences in the size of their introns ranging
from about 6kb to 50kb, but they each have 4 coding
exons. The human K-ras gene contain an alternative
fourth coding exon. Alternative RNA splicing specifies
either of two isomorphic proteins differing by 25 amino
acid residues at their carboxy-terminus. Ras genes are
expressed in all tissues, have a promotor region with
multiple GC boxes, but lack a TATA- or CCAT-box;
features resembling the promotors of housekeeping
genes (Lowndes et al., 1999).
A comparison of human H-, K-, and N-ras nucleotide
sequences with the corresponding regions in other
mammalian species reveals a remarkable sequence
similarity (Watzinger et al., 1998). All differences are
synonymous changes with no effect on the amino acid
Functional aspects of RAS proteins
Mammalian ras genes code for closely related, small
proteins of 189 amino acids with a molecular weight of
21,000 Daltons (p21). When the alternative exon of Hor K-ras is used, proteins of 170 or 188 amino acids are
synthesized. The molecular weight of the H-ras protein
variant is 19,000 Daltons and that of the K-ras variant
is not distinguishable from the normal RAS proteins.
RAS proteins are localized in the inner plasma
membrane, bind GDP and GTP and possess an intrinsic
GTPase activity, implicated in the regulation of their
activity. Because of the functional resemblance to GProteins, p21RAS
116
RAS family
Watzinger F, Lion T
Figure 1 Mechanism of RAS regulation.
deregulated activation of RAS proteins and oncogenic
transformation.
Another group of regulatory proteins involved in
stimulating the transition of RAS proteins from the
inactive- to the active GTP-bound state are designated
Guanine Nucleotide Exchange Factors (GEFs) or RASGRFs (guanine nucleotide releasing factors) (Satoh and
Kaziro, 1992). Normally, the release of GDP is
regulated by the intracellular concentration of GTP. An
increase in the GTP concentration leads to an enhanced
dissociation of GDP. GEFs catalyze the dissociation of
GDP (see Fig.1). A ligand-free RAS protein
immediately binds GTP, because it is 10-fold more
abundant in the cytosol than GDP.
The activity of RAS proteins is regulated by a cycle of
guanine nucleotide binding and 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 as a positive
regulator; GAP (GTPase activating protein) promotes
hydrolysis of GTP and acts as a negative regulator. Pi,
inorganic phosphate.
have been hypothesized to be also involved in different
types of ligand-mediated signal transduction pathways.
Later, RAS proteins were shown to influence
proliferation, differentiation, transformation, and
apoptosis by relaying mitogenic and growth signals into
the cytoplasm and the nucleolus (Khosravi Far and Der,
1994). In a normal cell most of the RAS molecules are
present in an inactive GDP-bound conformation. An
extracellular stimulus initiates the release of
GDP and the subsequent binding of GTP. This
conformational change enables the interaction with the
putative effector molecules and permits the transmission
of signals. Finally, the active GTP-bound state is turned
off by hydrolysis of GTP to GDP and inorganic
phosphate.
The intrinsic GTPase activity is rather weak, not
sufficiently effective for signal transduction pathways
where rapid inactivation is required. In order to
accelerate this low rate of hydrolysis (which is about
10-2 min-1) and to enable a transient burst of signalling
activity, regulatory proteins like GAPs (GTPase
activating proteins) (Ahmadian et al., 1996) or NF-1
(Neurofibromatosis Type 1) protein (McCormick,
1995), bind to the GTP-containing conformation and
stimulate the GTPase activity more than 100-fold. The
decreasing level of RAS-GTP, and hence, increasing
level of RAS-GDP complexes result in a loss of the
biological activity of RAS (see Fig. 1). In a normal cell,
GAPs help to keep most of p21RAS in an inactive
GDP-bound state. The finding that overexpression of
non-mutated ras genes can also transform cells supports
the idea that the abundance of GAPs is limited.
Overexpression of p21RAS could lead to saturation of
the regulatory proteins, resulting in a constitutive,
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(2)
Structure of RAS proteins
The alignment of their primary amino acid sequence
clearly indicates the presence of four domains within
the RAS molecules. The first domain includes 85
amino acids at the N-terminus which are found to be
identical in H-, K-, and N-ras, demonstrating a high
degree of conservation. The following 80 amino acids
form a second domain, showing less conservation (7080%) within the RAS proteins. The third domain spans
the rest of the molecule, except for the last four amino
acids, and represents a hypervariable region.
117
RAS family
Watzinger F, Lion T
Figure 2 Topological structure of p21.
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, Treedimentional 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 GTPbound 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.
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 of posttranslational modifications and forms the
last domain.
For more accurate identification of biologically relevant
regions of p21RAS and for the interpretation of
activating mutations, X-crystallographic analysis of
GDP- and GTP-bound RAS molecules and in vitro
mutagenesis studies with mutated or truncated RAS
proteins were performed. As a result of these studies,
the catalytic domain was identified between residues 1
to 171, including the region involved in guanine
nucleotide binding where 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
interactions with 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 for the attachment of p21RAS to the plasma
membrane.
Comparison of the crystal structure of RAS-GTP (as
indicated in Fig.2) and RAS-GDP complexes revealed
that switching between the active and the inactive state
is associated 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-GDP change,
indicating that this conformational change is necessary
for the transition of RAS from the GDP- to the GTPbound state and vice versa (Milburn et al., 1990;
Scheffzek et al., 1997).
The polypeptide chain of RAS p21 consists of six bstrands and five a-helices. Loop 1, alias phosphate-
Incidence of ras mutations
(See also the appendix).
Activating ras mutations can be found in human
malignancies with an overall frequency of 15-20%. A
high incidence of ras gene mutations has been reported
in malignant tumors of the pancreas (80-90%, K-ras)
118
RAS family
Watzinger F, Lion T
(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 neoplasia of myeloid origin (18-30%, Kand 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
breast carcinoma (0-12%, K-ras) (Rochlitz et al., 1989;
Spandidos, 1987), glioblastoma and neuroblastoma (010%, 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
Stomach
Frequency (%)
0-40
Urinary Bladder
0-65
Prostate
0-10
Skin
Thyroid
0-45
0-60
Breast
Head and neck
0-10
0-30
Endometrium
5
K-RAS mutations
Tumor
Pancreas
Colon and rectum
Frequency (%)
80-90
25-60
Lung
25-60
Prostate
0-25
Skin
Thyroid
0-25
0-60
Liver
10-25
Ovary
Endometrium
0-50
10-40
Kidney
Brain
0-50
0-15
Testis
(Seminoma)
Leukemia
(ANLL, MDS)
Urinary Bladder
Head and neck
Breast
10-45
5-15
5
10
10
References
(Deng et al., 1991; Kim et al., 1997; Miki et al., 1991; Nanus et al.,
1990; Victor et al., 1990)
(Hong et al., 1996; Malone et al., 1985; Olderoy et al., 1998; Saito et
al., 1997; Visvanathan et al., 1988)
(Carter et al., 1990; Gumerlock et al., 1991; Konishi et al., 1997;
Shiraishi et al., 1998)
(Campbell et al., 1993; Tormanen and Pfeifer, 1992)
(Bouras et al., 1998; Capella et al., 1996; Fusco et al., 1987; Lemoine
et al., 1988; Lemoine et al., 1989; Suarez et al., 1988)
(Kraus et al., 1984; Spandidos, 1987)
(Clark et al., 1993; Kiaris et al., 1995; Rumsby et al., 1990; Saranath et
al., 1991)
(Varras et al., 1996)
Reference
(Almoguera et al., 1988; Smit et al., 1988; Watanabe et al., 1996)
(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)
(Husgafvel-Pursiainen et al., 1992; Rodenhuis and Slebos, 1992;
Rodenhuis et al., 1997; Sagawa et al., 1998; Suzuki et al., 1990)
(Capella et al., 1991; Carter et al., 1990; Gumerlock et al., 1991;
Konishi et al., 1992; Konishi et al., 1997; Shiraishi et al., 1998)
(Albino et al., 1991; Shukla et al., 1989)
(Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine
et al., 1989; Suarez et al., 1988)
(Challen et al., 1992; Marion et al., 1991; Tada et al., 1990; Tada et al.,
1992)
(Enomoto et al., 1991; Ichikawa et al., 1994; Teneriello et al., 1993)
(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)
(Nagata et al., 1990; Skalkeas et al., 1991)
(Ballas et al., 1988; Ballas et al., 1988; Brustle et al., 1996; Ireland,
1989; Maltzman et al., 1997)
(Moul et al., 1992; Mulder et al., 1989; Ridanpaa et al., 1993)
(Nakagawa et al., 1992; Neubauer et al., 1994; Padua et al., 1998; Sheng
et al., 1997)
(Olderoy et al., 1998)
(Rathcke et al., 1996; Rumsby et al., 1990)
(Dawson et al., 1996)
Atlas Genet Cytogenet Oncol Haematol. 1999; 3(2)
119
RAS family
N-RAS mutations
Tumor
Leukemia ANLL,
MDS
Watzinger F, Lion T
Frequency (%)
20-40
Leukemia
CML,ALL
Brain
0-10
Skin
0-20
Thyroid
0-60
Testis
Stomach
Liver
0-40
(gastric tumors) 5
0-15
0-15
Reference
(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)
(Watzinger et al., 1994; Yokota et al., 1998)
(Ballas et al., 1988; Bos, 1988; Brustle et al., 1996; Ireland, 1989;
Maltzman et al., 1997)
(Albino et al., 1984; Mooy et al., 1991; Soparker et al., 1993; van't
Veer et al., 1989)
(Capella et al., 1996; Fusco et al., 1987; Lemoine et al., 1988; Lemoine
et al., 1989; Suarez et al., 1988)
(Moul et al., 1992; Mulder et al., 1989; Ridanpaa et al., 1993)
(Kim et al., 1997)
(Challen et al., 1992; Tada et al., 1990; Tada et al., 1992)
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