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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 2971-2980
REVIEW ARTICLE
Ras Proteins: Recent Advances and New Functions
By
Angelita Rebollo and
Carlos Martínez-A
From Centro Nacional de Biotecnología, Department of
Immunology and Oncology, Campus de Cantoblanco, Madrid, Spain.
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INTRODUCTION |
THE RAS FAMILY comprises H-Ras, K-Ras 4A,
K-Ras 4B, N-Ras, and other homologous proteins such as R-Ras, TC21,
Rap, and Ral. Ras protein function is controlled by a guanosine
triphosphate-guanosine diphosphate (GTP-GDP) cycle that is
regulated by at least 2 distinct classes of regulatory
proteins.1 First, a GTPase-activating protein recognizes
the active GTP-bound protein and stimulates the intrinsic GTPase
activity of Ras to form the inactive GDP-bound protein. Second, guanine
nucleotide exchange factors promote the formation of the active
GTP-bound state.2
Ras proteins are proto-oncogene products that are critical components
of signaling pathways leading from cell-surface receptors to the
control of cellular proliferation, differentiation, or cell death.
Ligand-stimulated activation of the cell-surface receptor, receptor-associated tyrosine kinases, or agonist mediated through G
protein-coupled receptors results in the activation of Ras
proteins.3,4 Activated Ras, in turn, stimulates a cascade
of serine/threonine kinases to initiate transcriptional activation of
genes. Several proteins with Src homology domains (SH2 and SH3), which
mediate protein-protein interaction, have been implicated as connectors of the pathway.5
In this review, we will provide an overview of our current knowledge of
the role of Ras proteins in signal transduction leading to
proliferation or apoptotic cell death. We will discuss recent observations concerning the functional role of Ras modifications and
the regulatory proteins that control Ras activity as well as the
intracellular signaling pathways that are mediated by Ras proteins,
with special mention of hematopoietic cells.
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RAS C-TERMINAL POSTTRANSLATIONAL MODIFICATIONS AND THEIR FUNCTIONAL
SIGNIFICANCE |
Ras proteins are posttranslationally modified by prenylation, a process
that involves the addition of a 15-carbon farnesyl isoprenoid moiety to
a conserved cysteine residue in a C-terminal CAAX motif by a farnesyl
protein transferase (FPT). After prenylation, the C-terminal tripeptide
is removed by proteolysis and the newly exposed C-terminal is
methylated
(Fig
1). Ras prenylation is thought to facilitate membrane targeting and to
be essential for Ras function.6,7 In addition, this
modification can have important consequences for protein-protein
interactions.8,9 In the same context, several reports have
presented biochemical evidence for a prenylation-dependent interaction
of Ras proteins with protein acceptors in the cytoplasmic membrane and
with guanine nucleotide exchange factors and effectors.10 Ras isoprenylation appears not to be essential for transformation, because it can be replaced by a different type of plasma membrane targeting signal, such as the addition of a transmembrane
domain.11
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| Fig 1.
C-terminal modifications of Ras proteins. A farnesyl
group is added to the cysteine of the C-terminal CAAAX motif. The
C-terminal tripeptide is removed by proteolysis and the newly exposed
cysteine residue is methylated. Ras proteins can be further
palmitoylated or phosphorylated.
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| Fig 2.
Schematic view of Ras regulatory factors. Ras proteins
cycle between the active GTP-bound and the inactive GDP-bound state.
Exchange factors catalyze the activation of Ras inducing the
dissociation of GDP. NO may also promote the formation of Ras-GTP. Ras
remains active until bound GTP is hydrolyzed to GDP, a process that is
accelerated by GTPase activating proteins.
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| Fig 3.
Summary of candidate Ras effectors. The complexity of the
signal pathways triggered by Ras is evidenced by the multiple
downstream effectors. PLD, phospholipase D; PIP, phosphatidylinositol
phosphate; SRF, serum response factor.
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The various Ras proteins also present some differences in their
posttranslational processing. Prenylated H-Ras and N-Ras proteins can
be further lipidated by palmitoylation, a reversible modification that
could improve the association of these proteins to the plasma membrane.
In contrast, K-Ras proteins are not palmitoylated, but possess a
polybasic domain that can be reversibly phosphorylated.12 Ras proteins also differ in their affinity for FPT in vitro and in
their sensitivity to FPT inhibitors, because K- and N-Ras can be
alternatively geranylgeranylated in cells treated with FPT inhibitors.13-17 In addition, K-Ras can be both
geranylgeranylated or farnesylated in vivo.18 Both
farnesyltransferase and geranylgeranyltransferase inhibitors are
required for inhibition of oncogenic K-Ras prenylation, but each alone
is sufficient to suppress human tumor growth in the nude
mouse.19 Interestingly, nonfarnesylated H-Ras can be palmitoylated and trigger differentiation and transformation, suggesting that farnesyl is not needed as a signal for palmytate attachment and that palmytate can support H-Ras membrane binding and 2 different biological functions.20
Recently, novel mechanisms for the regulation of Ras processing have
been proposed. Induction of isoprenoid biosynthetic pathways by
lipoprotein depletion can upregulate the farnesylation and membrane
association of Ras.21 Conversely, cholesterol enrichment may lead to a reduction in Ras farnesylation and membrane association.
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REGULATORS OF THE RAS-GTP/GDP CYCLE |
In addition to posttranslational modifications, Ras proteins require
binding of GTP to develop functional activity. Switching between the
active GTP-bound and the inactive GDP-bound state is regulated by
binding to guanine nucleotide. Although Ras proteins possess intrinsic
GTPase and GDP/GTP exchange activities, they are too low to account for
the rapid and transient GDP/GTP cycling that occurs during mitogenic
stimulation. Instead, a complete model for Ras function includes
regulatory proteins that control the GTP/GDP cycling
rate.22 These regulatory proteins include GTPase activating
proteins (GAPs), which stimulate hydrolysis of bound GTP to
GDP,23 and guanine nucleotide exchange factor proteins,
which promote the replacement of bound GDP with GTP24 (Fig
2).
Two distinct GAPs for Ras proteins have been identified: p120GAP, a
predominantly cytosolic protein, with a catalytic C-terminal domain
that contains the Ras-binding domain and interacts with the Ras
effector domain. The N-terminal domain regulates the activity of the
catalytic domain and interacts with downstream effectors. This domain
has 2 SH2 and 1 SH3 domain and a pleckstrin homology (PH) domain. In
addition to their roles as negative regulators of Ras, it is believed
that GAPs can operate as downstream effectors of Ras.25 The
first evidence for a role of GAPs as Ras effectors came from the
observation that oncogenic Ras mutants still require GAP interaction
for their transforming activity. In addition, Ras-transforming activity
can be blocked by Rap1 by competing for binding to p120GAP. The
effector function of p120GAP is located in the N-terminal regulatory
domain, which interacts with receptor and nonreceptor tyrosine kinases,
as well as with phosphorylated proteins.26,27 All of these
results are incorporated into a proposed model that suggests binding of
Ras-GTP to the catalytic domain of p120GAP. This binding results in
conformational changes that expose the SH2/SH3 domains for interaction
with downstream effectors.
The RasGAP NF1 shares both sequence identity and substrate specificity
with the p120GAP C-terminal catalytic domain. Less is known about the
functions of NF1 and it can be assumed that each protein mediates
distinct pathways. While growth factor stimulates tyrosine
phosphorylation of p120GAP, serine and threonine phosphorylation has
been reported for NF1. In addition to its role as a negative regulator
of Ras activity, NF1 regulates proliferation and survival of precursors
and lineage-restricted myeloid progenitors in response to multiple
cytokines by modulating Ras output.28 Loss of NF1 gene is
found in some patients with juvenile chronic myelogenous leukemia
(JCML). Deficiency in NF1 also induces myeloproliferative disease
through Ras-mediated hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF).29
Likewise, NF1 / mouse embryos show an
aberrant growth of hematopoietic cells, suggesting that NF1 is required
to downregulate Ras activation in myeloid cells exposed to GM-CSF,
interleukin-3 (IL-3), or stem cell factor (SCF).30 Finally,
NF1 inactivation cooperates with N-Ras in lymphogenesis by a mechanism
independent of its GTPase activity.31 The observed
cooperation emphasizes the importance of searching for additional
functions of NF1. Another RasGAP, Gap1m, with specific GTPase activity for H- and R-Ras, stimulates the GTPase activity of Ras
better than it does that of R-Ras. The high affinity of Gap1m for the
substrates and its membrane localization suggests that Gap1m may
regulate the basal activity of both H- and R-Ras.32
The third class of regulatory proteins controlling the RasGDP/GTP cycle
includes the guanine nucleotide dissociation inhibitor (Ras GDI). Ras
GDI is a negative regulator of Ras activity because of its potent
ability to inhibit dissociation of bound GDP. This factor inhibits GDS,
but not GAP, activity of Ras.33
As mentioned above, Ras proteins have low intrinsic exchange activity,
increased by the binding of positive regulators. The first regulatory
factor isolated that enhances and controls RasGDP/GTP exchange was the
yeast cdc25 gene.34 Cdc25 activates H-Ras in vivo, but not
N- or K-Ras. Selective activation of a single Ras homologue by cdc25
suggests that each Ras protein participates in a different signal
transduction pathway. Sos1 and 2, which couple tyrosine kinase
receptors with Ras activation, are also guanine nucleotide exchange
factors. Sos activity is regulated by intracellular
interactions35-37 and by phosphorylation after growth-factor stimulation of the cells. In addition to MAK kinases, p90Rsk-2 can phosphorylate Sos.38 Finally, Sos activity is
inhibited in vitro by binding of phosphatidylinositol 4, 5-P2 to the PH domain.39
The direct posttranslational modification of Ras by nitric oxide (NO)
promotes Ras activation. Ras can be single nitrosylated at Cys 118 by
NO resulting in stimulation of guanine nucleotide exchange and
activation of downstream signaling,40 possibly by
destabilizing interaction between residues in the GDP-binding pocket
and the nucleotide. This suggests that Ras function may be regulated
directly by changes in the redox state of the cell.
A guanyl nucleotide-releasing protein for Ras, Ras-GRP, has been
described recently, which has a calcium and diacylglycerol binding
domain, activates Ras, and causes transformation. RasGRP may couple
changes in diacylglycerol and possibly calcium concentrations to Ras
activation.24,41 Finally, contradictory data exist
concerning the role of Vav as a RasGDS. While some groups describe Vav
as a RasGDS that activates Ras after T-cell receptor
activation,42 other groups suggest that Vav cooperates with
Ras in transformation but is not a GDP/GTP exchange factor for
Ras.43
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CANDIDATE EFFECTORS OF RAS |
Signaling pathways transmitted through Ras further activate Ras
effector molecules, the best characterized of which is the serine/threonine kinase Raf. Through interaction with Raf, Ras activates the MEK1 and 2 kinases and, in turn, the ERK1 and 2 kinases.
ERKs phosphorylate cytoplasmic targets such as Rsk, Mnk, and
phospholipase A244-46 and translocate to the nucleus, where they stimulate the activity of various transcription factors (Fig 3).
The Raf zinc finger is not required for plasma recruitment by Ras, but
is essential for full activation of Raf at the cytoplasmic membrane,
suggesting that Ras has 2 separate roles in Raf activation: recruitment
of Raf to the plasma membrane through interaction with the Ras-binding
domain, and activation of membrane-localized Raf via a mechanism that
requires the Raf zinc finger.47 It has been shown that Ras
interacts through the effector domain with 2 distinct N-terminal
regions of Raf,48,49 suggesting that Ras promotes more than
membrane translocation of Raf.50 Among other components
that contribute to Raf activation, we can include the 14-3-3 proteins
and phospholipids.51 The MAPK kinase pathway is critical in
mediating signals from Ras/Raf; however, Ras mutants have shown that
the PI3 kinase pathway synergizes with the Raf pathway to induce
proliferation and loss of contact inhibition.52 Similarly,
it has been shown that activation of Raf and ERK is not needed for Ras
to induce membrane ruffling, suggesting that Ras could regulate both
Raf-dependent and Raf-independent signals.53
Ras isoforms vary in their ability to activate Raf; K-Ras recruits Raf
to the plasma membrane more efficiently than does H-Ras, and H-Ras is a
more potent activator of PI3 kinase than is K-Ras. This suggests that
activation of different Ras isoforms can have distinct biochemical
consequences for the cell.54 In this context, it has been
suggested that the subcellular distribution of Ras proteins could be
related to differential participation of various Ras homologues in
signaling processes. Raf-1 is not only activated in mitogenic pathways
leading to cell-cycle entry, but also during mitosis. Transient
expression experiments have shown that, in contrast to
growth-factor-dependent activation of Raf-1, mitotic activation of
Raf-1 is Ras-independent. In mitosis, activated Raf-1 is located
predominantly in the cytoplasm, in contrast to mitogen-activated Raf-1,
which is bound to the plasma membrane. Mitotic activation of Raf-1 is
partially dependent on tyrosine phosphorylation and does not signal via
the MAP kinase pathway.55
Using mutants of Ras and Raf that affect physical association, it has
been shown that activated Ras stimulates the kinase activity of
membrane-targeted Raf only when both molecules interact physically.56 The mechanism by which Ras interaction with
Raf enhances Raf activity may operate by induction of conformational changes in Raf, exposing residues that are substrates for activation of
kinases; alternatively, Ras may participate in the assembly of a
signaling complex between Raf and other proteins. It has been also
shown that Raf activation by Ras can occur in the absence of
phosphorylation. In contrast, Raf activation by Src kinase is
accompanied by tyrosine phosphorylation, suggesting that activation of
Raf by Ras or Src occurs through different mechanisms.57 Finally, Rap1A, which has an effector domain identical to that of Ras,
cannot activate Raf and even antagonizes several Ras functions in vivo.
Rap1A interferes with Ras-dependent activation of Raf by inhibiting Ras
binding to a cysteine-rich region of Raf.58 On the
contrary, it has been reported that Rap1 mediates sustained MAP kinase
activation induced by nerve growth factor via activation of
B-Raf.59
In addition to controlling Raf kinases, Ras also regulates other
proteins such as PI3 kinase.60 Ras interacts with at least 4 different p110 subunits of PI3 kinase. The domain of PI3 kinase interacting with Ras is located between amino acids 133 and 314. Mutants in this region show differential impairment of effector interaction providing information concerning the contribution of Ras
effectors to Ras function.61 This interaction in turn activates the serine/threonine kinase Akt/PKB.62 PI3
kinase-dependent activation of Ras also controls the activity of Rac
and p70s6k. In addition to Raf and PI3 kinase, other Ras
effectors have been described. These include Rin1,63
p120GAP,25 AF6,64,65 Ral GDS,66
Nore1,67 Rlf,68 and PKC .69
PKC is an atypical protein kinase C isoform that is
calcium-independent and unresponsive to phorbol esters. PKC is
structurally similar to Raf and has been reported to have mitogenic
effects in Ras-dependent oocyte maturation. Regulatory regions of
PKC associate with Ras-GTP, suggesting that Ras-GTP localizes PKC
to the plasma membrane, where it may be activated by PtdIns P3. Raf
activation by PKC was not blocked by dominant negative Ras, indicating
that PKC activates Raf by a mechanism distinct from that initiated by
activation of receptor tyrosine kinases.70
Rin1 directly interacts in vivo with H-Ras in a GTP- and effector
domain-dependent fashion and competes with Raf for in vitro binding to
Ras. The domain of Rin1 that binds Ras also binds the 14-3-3 protein,
suggesting that Rin1 can interact with multiple signaling molecules.
Rin1 also interacts with Abl and Bcr through a domain distinct from the
Ras binding domain.71,72 Nore1 has recently been identified
as a potential Ras effector. Nore1 interacts directly with Ras in vitro
in a GTP-dependent manner; this interaction also requires an intact Ras
effector domain.67 Ras/Nore1 association also occurs in
vivo after EGF receptor activation. Rlf has been described as an
effector of Ras that functions as an exchange factor for
Ral.68 A constitutively active form of Rlf can stimulate transcriptional activation and cell growth. AF6 was identified by the
yeast 2-hybrid screening.64,65 The N-terminal domain of AF6
interacts with Ras-GTP and this interaction interferes with the binding
of Ras to Raf. It has recently been shown that stimulation of EGF
receptor results in a rapid activation of Ral, that correlates with the
activation of Ras.73 Finally, Sos facilitates the exchange
of Ras nucleotide and couples Ras to Rac through its Dbl and pleckstrin
homology domains (PH) in a PI3 kinase-dependent manner.74
Other Ras effectors have been identified that could contribute to Ras
regulation. Ras interacts with the N-Jun amino-terminal kinase
(JNK).75 Ras also interacts with MEK kinase,76
Bcl-2,77,78 REKS (Ras-dependent extracellular
signal-regulated kinase kinase stimulator),79 and KSR
(kinase suppressor of Ras or ceramide-activated protein
kinase).80,81 KSR is a positive regulator of Ras signaling that functions between Ras and Raf or in a parallel pathway to Raf.82 KSR is a potent modulator of a signaling pathway
essential to cell growth and development.83 This kinase
contains 5 consensus sites of phosphorylation by mitogen-activated
protein kinase, suggesting that KSR is an in vivo substrate of MAP
kinases.84 It has been shown that KSR, the dimeric protein
14-3-3, and Raf form an oligomeric signaling complex that positively
regulates the Ras signaling pathway.85 Finally, using the
yeast 2-hybrid method, we have shown that Ras interacts with the
transcription factor Aiolos. IL-2 deprivation induces Ras/Aiolos
association and, consequently, inhibition of Bcl-2 expression,
resulting in apoptotic cell death. One of the functional consequences
of Ras/Aiolos interaction is the translocation inhibition of Aiolos
from the cytoplasm to the nucleus. Our results suggest a novel role for Ras as a blocker of Bcl-2 expression through the cytoplasmic
sequestering of Aiolos.86
Other important targets for Ras signals are the transcription factors
NFAT and NF B. NFAT proteins are cytosolic but, in response to
receptor stimulation, they translocate to the nucleus, where they form
transcriptionally active complexes with proteins of the Jun and Fos
family of transcription factors. Activation of NFAT requires the
coordinated interaction of the Ras signaling and the
calcium/calcineurin pathways, suggesting that activation of NFAT
requires the action of multiple Ras effector pathways.87,88 NF-B is activated in response to many extracellular stimuli and is
involved in the regulation of cytokine, chemokine, and growth-factor genes.89 NF-B has been shown to have antiapoptotic
effects. In NF-B-deficient cells, as well as in cells expressing a
dominant negative IB , the apoptotic responses to external stimuli
are enhanced.90 The proposed mechanism for the
antiapoptotic effect of NF-B is the transcriptional regulation of
specific genes that are antiapoptotic. The ability of activated Ras to
transform p53 null cells is dependent on the ability of Ras to activate
NF-B. Thus, there are cell death pathways that can be initiated by
Ras after the inactivation of NF-B.91 Oncogenic H-Ras
activates NF-B, which is required for cellular transformation,
suggesting that NF-B is a critical downstream mediator of H-Ras
signaling.92 There is also evidence that, in some cell
types, NF-B can be a proapoptotic molecule.
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ANTIAPOPTOTIC AND PROAPOPTOTIC RAS-MEDIATED PATHWAYS |
Ras proteins have been involved in both the protection and the
promotion of apoptosis. This apparent contradiction is solved by the
ability of Ras to regulate multiple signaling pathways through the
interaction with different effectors.93 Ras activation results in the induction of cyclin D1 expression.94-96 Ras
also plays an important role in the downregulation of the cdk inhibitor p27 kip, possibly through the MAPK-mediated phosphorylation of p27kip,
which prevents binding of the cdk2 inhibitor and may induce p27kip
degradation.97,98 Recent studies link Ras function to the
retinoblastoma (Rb) cell-cycle checkpoint,99,100
establishing a link between Ras and cdk/Rb/E2F pathway.101
Oncogenic Ras also causes growth arrest and premature senescence
associated with upregulation of p53 and p16 ink.102
Ras also mediates the signaling pathway responsible for phosphorylation
and activation of the cdc25 phosphoserine phosphatase. To become
activated, cdks need to be dephosphorylated by the cdc25 phosphatases
A, B, and C, regulating the progression through G2/M transition.103 All 3 phosphatases have been found in
association with Raf, an interaction that may be facilitated by the
14-3-3 protein.104 Finally, using dominant negative and
constitutive active Ras mutants, it has been shown that Ras regulates
c-Myc expression.105 Coexpression of Ras and Myc induces
cyclin-E-dependent kinase activity and transition to S
phase.106
On the other hand, Ras can also mediate antiproliferative effects. Ras
activation can induce p21cip expression and G1 arrest.107 In PC12 cells, the extent and duration of Ras activation determines whether cells proliferate or differentiate. Treatment of cells with EGF
leads to transient activation of Ras and proliferation while
stimulation with NGF results in a sustained activation of Ras, which
leads to differentiation.108,109 It it has been shown that
NGF acts via Ras and PI3 K in sensory neurons.110 Finally, activated Ras is detected in growth-factor-stimulated T and B cells.111,112 The antiapoptotic activity of Ras has been
linked to its ability to activate PI3 K. The PI3K-mediated survival
signal is mediated by the activation of Akt/PKB, a serine/threonine
kinase activated by PtdIns-3,4 P2.113-115 However, there is
also evidence that Akt/PKB can be activated in a PI3K-independent
fashion, thus raising the possibility that Akt/PKB-mediated protection
from apoptosis can also occur without PI3K activation. Akt/PKB
activation is involved in prevention of apoptosis in IL-4-stimulated
cells because overexpression of wild-type or constitutively active Akt mutants protect cells from IL-4 deprivation-induced apoptosis. Moreover, overexpression of a constitutively active Akt mutant in
IL-4-deprived cells correlates with inhibition of JNK2
activity.115 Akt/PKB inhibits the activation of caspases,
which are required for the apoptotic response to serum
withdrawal.116 One mechanism for Akt/PKB protection against
apoptosis is the phosphorylation and inactivation of Bad, a
proapoptotic Bcl-2 family member.117,118 PI3K/Akt is also
implicated as a key mediator of the aberrant survival of Ras
transformed cells in the absence of attachment and mediates
matrix-induced survival of normal cells.119,120 Ras-regulated expression of the transcription factor NFIL3 inhibits apoptosis without affecting Bcl-x expression in pro-B lymphocytes, indicating that multiple independent pathways mediate survival of
developing B cells.121 In agreement, recent studies have
shown that different downstream Ras pathways mediate the antiapoptotic function of Ras in IL-3-dependent hematopoietic cells.122
Oncogenic Ras also causes resistance to the growth inhibitor
insulinlike growth factor binding protein-3 (IGFBP-3), a possible
factor involved in the dysregulation of breast cancer cell
growth.123 Finally, IL-2- and IL-3-dependent cells are
protected from starvation-induced apoptosis by activated Ras through
upregulation of Bcl-2 and Bcl-X expression.124,125 This
protection is probably due to the association Raf/Bcl-2.126,127
The interaction between Ras and JNK in relation to the induction of
apoptosis is not clear. JNK activation may promote different cellular
consequences depending on the cell type or the activation of
complementary pathways. It is not completely understood whether JNK
activation is a cause or consequence of apoptosis.128-130
IL-2 deprivation correlates with an increase in JNK1 activity directly related to the induction of apoptosis.131 By contrast,
activation of the ERK pathway suppresses the activity of JNK and
promotes cell survival.128 However, it has also been shown
that inhibition of JNK activation can impair Ras transformation,
suggesting a growth-promoting role for this kinase.132
Ras activation has also been involved in the induction of apoptosis.
Ras mediates signals triggered by activation of the cell death receptor
Fas133 and overexpression of activated Ras leads to
increased Fas ligand expression.134 Ras activation is also linked to the induction of apoptosis in the phaechromocytoma cell line
PC12, which are rescued from apoptosis after expression of a dominant
negative Ras mutant.135 In T cells, Ras is activated following both IL-2 stimulation and deprivation, leading either to cell
proliferation or apoptosis, depending on whether other stimuli are
acting simultaneously.136
In parallel with the model proposed for the proto-oncogene c-Myc, it is
possible that 2 different Ras-mediated pathways may be triggered by an
external stimulus, 1 involved in proliferation and the other in
apoptosis. Alternatively, Ras may simultaneously induce both
proliferation and apoptosis, the latter blocked by the action of
survival factors, or Ras may induce either proliferation or apoptosis,
depending on external signals (Fig 4).
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| Fig 4.
Ras induces proliferation or apoptosis. Two different
Ras-mediated pathways may be triggered by an external stimulus, one
involved in proliferation and the other in apoptosis. Alternatively,
Ras may simultaneously induce both proliferation and apoptosis, the
latter blocked by the action of survival factors, or Ras may induce
either proliferation or apoptosis, depending on other simultaneous
external signals.
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HOMOLOGUE-SPECIFIC ROLES OF RAS PROTEINS |
The H-, N-, and K-Ras genes are ubiquitously expressed in mammalian
cells. A number of recent works suggest that the different Ras
homologues could preferentially mediate distinct cellular processes.
K-Ras, but not H- or N-Ras, plays an essential role in mouse
development.137-139 K-Ras is induced during differentiation of pluripotent embryonal stem cells. Its expression during early embryogenesis is limited temporally in a tissue-specific
distribution.140 K-Ras/ mice have defects in
myocardial cell proliferation and neuronal programmed cell death.
Erythroid cells from these embryos are able to achieve end-stage
differentiation within the hepatic microenvironment. K-Ras has been
described to specifically interact with microtubules141 and
disrupts basolateral polarity in colon epithelial cells.142
Selective activation of H-Ras by Ras-GRF has been reported, suggesting
the potential participation of each Ras homologue in different
signaling pathways.143 This hypothesis is supported by
recent findings showing a differential ability of the 4 Ras homologues
to induce focus formation, cell migration, or anchorage-dependent cell
growth.144 It has recently been found that Ras homologues
vary in their ability to activate the key effectors Raf-1 and
PI3K,145 with K-Ras being more effective as a recruiter and
activator of Raf-1 and H-Ras being more effective as an activator of
PI3K.99 In addition, selective activation of K-Ras
expression attenuates the ability of EGF receptor to activate MAP
kinase pathway by interfering with the receptor
autophosphorylation146; K-Ras also modulates the cell cycle
via both positive and negative regulatory pathways.147
Finally, K-Ras amplification was detected in mammary tumor
progression.148 H-Ras, but not N-Ras, is involved in the
IL-3-dependent signaling pathway implicated in integrin activation.149 Moreover, H-Ras stimulates tumor
angiogenesis by 2 distinct pathways.150 The activated
H-Ras-induced factor-independent growth of myeloid cells requires the
activation of at least 2 pathways, 1 inhibiting factor-withdrawal
apoptosis and other causing cell-cycle progression.151
Moreover, the transforming activity of Ras can be suppressed through
ERK dephosphorylation.152 Cell-specific differences in the
intrinsic transforming potential of N-, H-, and K-Ras153 as
well as in the different capacity of H- and N-Ras to regulate MAP
kinase activity154 have also been reported. In this context, results from our laboratory have evidenced distinct behavior of Ras homologues in T cells undergoing apoptosis in response
to IL-2 deprivation, with K-Ras present in mitochondria only in
IL-2-stimulated cells and H-Ras being observed in mitochondria only
upon IL-2 deprivation.78 Mutations of N-Ras may be involved in the pathogenesis of JCML155 as well as in acute
myelogenous leukemia (AML),156 suggesting that point
mutations in Ras gene might affect signal transduction through GM-CSF.
In addition, N-Ras mutation induces myeloproliferative disorders and
apoptosis in bone marrow repopulated mice.157 The results
are consistent with a model in which antiproliferative effects are the
primary consequence of N-Ras mutations and secondary transforming
events are necessary for the development of AML. Moreover, erythroid progenitor cells expressing mutated N-Ras exhibit a proliferative defect resulting in an increased cell doubling time and a decrease in
the proportion of cells in S/G2 phase of the cell cycle.158 Finally, activated K-Ras-mediated signals are involved in the SEK-JNK
pathway that are distinct from that involved in MEK-ERK activation in
human colon cancer cells. The imbalance between ERK and JNK activity
caused by activated K-Ras may play a critical role in human
tumorigenesis.159
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ACKNOWLEDGMENT |
We thank Drs P. Martinez for critical reading of the manuscript and C. Mark for editorial assistance.
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FOOTNOTES |
Submitted April 29, 1999; accepted June 29, 1999.
The Department of Immunology and Oncology was founded and is supported
by the Spanish Research Council (CSIC) and Pharmacia & Upjohn.
Address reprint requests to Angelita Rebollo, Centro Nacional de
Biotecnología, Department of Immunology and Oncology,
Universidad Autónoma, Campus de Cantoblanco, E-28049 Madrid,
Spain; e-mail: arebollo{at}cnb.uam.es.
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TOP
INTRODUCTION
RAS C-TERMINAL...