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.

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 (Fig1). 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.10Ras 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 

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.

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.

Close modal
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.

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.

Close modal
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.

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.

Close modal

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.12Ras 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.

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 (Fig2).

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).29Likewise, 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 

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.57Finally, 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 Rin1,63p120GAP,25 AF6,64,65 Ral GDS,66Nore1,67 Rlf,68 and PKCζ.69PKCζ is an atypical protein kinase C isoform that is calcium-independent and unresponsive to phorbol esters. PKCζ is structurally similar to Raf and has been reported to have mitogenic effects in Ras-dependent oocyte maturation. Regulatory regions of PKCζ associate with Ras-GTP, suggesting that Ras-GTP localizes PKCζ 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,76Bcl-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 NFκB. 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.87,88NF-κB is activated in response to many extracellular stimuli and is involved in the regulation of cytokine, chemokine, and growth-factor genes.89 NF-κB has been shown to have antiapoptotic effects. In NF-κB–deficient cells, as well as in cells expressing a dominant negative IκBα, the apoptotic responses to external stimuli are enhanced.90 The proposed mechanism for the antiapoptotic effect of NF-κB 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-κB. Thus, there are cell death pathways that can be initiated by Ras after the inactivation of NF-κB.91 Oncogenic H-Ras activates NF-κB, which is required for cellular transformation, suggesting that NF-κB is a critical downstream mediator of H-Ras signaling.92 There is also evidence that, in some cell types, NF-κB can be a proapoptotic molecule.

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,99,100establishing a link between Ras and cdk/Rb/E2F pathway.101Oncogenic 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.107In 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.119,120Ras-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.122Oncogenic 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.128-130IL-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).

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.

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.

Close modal

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.142Selective 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.147Finally, 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.151Moreover, 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.158Finally, 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 

We thank Drs P. Martinez for critical reading of the manuscript and C. Mark for editorial assistance.

The Department of Immunology and Oncology was founded and is supported by the Spanish Research Council (CSIC) and Pharmacia & Upjohn.

1
McCormick
F
Going for the GAP.
Curr Biol
8
1998
673
2
Wittinghofer
A
Signal transduction via Ras.
Biol Chem
379
1998
933
3
Hall
A
G proteins and small GTPases: Distant relatives keep in touch.
Science
279
1998
509
4
McCormick
F
Ras biology in atomic detail.
Nat Struct Biol
3
1996
653
5
Pawson
T
Gish
GD
SH2 and SH3 domains: From structure to function.
Cell
71
1992
359
6
Ashby
MN
CAAX converting enzymes.
Curr Opin Lipidol
9
1998
99
7
Dumphy
JT
Linder
ME
Signaling function of protein palmitoylation.
Biochim Biophys Acta
1436
1998
245
8
Gordon
JI
Duronio
RJ
Rudnick
DA
Adams
SP
Goker
GW
Protein N-myristoilation.
J Biol Chem
266
1991
8647
9
Zang
FL
Casey
PJ
Protein prenylation: Molecular mechanism and functional consequences.
Annu Rev Biochem
65
1996
241
10
Okada
T
Maguda
T
Shinkai
M
Kariya
T
Kataoka
T
Post-translational modification of H-Ras is required for activation, but not for association with B-Raf.
J Biol Chem
271
1996
4671
11
Hart
KC
Donogue
DJ
Derivatives of activated H-Ras lacking C-terminal lipid modifications retain transforming ability if targeted to the correct subcellular location.
Oncogene
14
1997
954
12
Glomste
JA
Farnsworth
CC
Role of protein modification reactions in programming interactions between Ras-related GRPases and cell membrane.
Annu Rev Cell Biol
10
1994
181
13
White
DB
Kirschmeier
P
Hockenberry
TN
Nuñez-Oliva
I
James
L
Catino
JJ
Bishop
WB
Pai
JK
K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors.
J Biol Chem
272
1997
14459
14
Lerner
EC
Zang
TT
Knowles
DB
Quian
Y
Hamilton
AD
Sebti
SM
Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cells.
Oncogene
15
1997
1283
15
Zang
FL
Kirschmeier
P
Carr
D
James
L
Bond
RW
Wang
L
Patton
R
Windsor
W
Syto
R
Zhang
R
Bishop
WR
Characterization of H-Ras, N-Ras, K-Ras4A and K-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I.
J Biol Chem
272
1997
10232
16
Kohl
NE
Omer
CA
Conner
MW
Anthony
NJ
Davide
PJ
Solms
SJ
Giuliani
EA
Gomez
RP
Graham
SL
Hamilton
K
Inhibition of farnesyltransferase induces repression of mammary carcinomas in Ras transgenic mice.
Oncogene
17
1998
1233
17
Siddqui
AA
Garland
JR
Dalton
MB
Sinensky
M
Evidence for a high affinity, saturable prenylation-dependent p21 ras binding site in plasma membrane.
J Biol Chem
273
1998
3712
18
Rowell
CA
Kowalczyk
JJ
Lewis
MD
Garcia
A
Direct demonstration of geranylgeranylation and farnesylation of K-Ras in vivo.
J Biol Chem
272
1997
14093
19
Sun
J
Quian
Y
Hamilton
AD
Sebti
SM
Both farnesyltransferase and geranyltransferase inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts.
Oncogene
16
1998
1467
20
Booden
MA
Baker
TL
Solski
PA
Der
JC
Punke
SG
Buss
JE
A non-farnesylated H-Ras protein can be palmytoilated and trigger potent differentiation and transformation.
J Biol Chem
274
1999
1423
21
Gadbut
AP
Wu
L
Tang
D
Papageorge
A
Watson
JA
Galper
JB
Induction of the cholesterol metabolic pathway regulates the farnesylation of Ras in embryonic chick heart cells: A new role for Ras in regulating the expression of muscarinic receptors and G proteins.
EMBO J
16
1997
7250
22
Scheffzek
K
Ahmadian
MR
Wittinghofer
A
GTPase-activating proteins: Helping hands to complement an active site.
Trends Biochem Sci
23
1998
257
23
Wittinghofer
A
Scheffzek
K
Ahmadian
MR
The interaction of Ras with GTPase-activating proteins.
FEBS Lett
410
1997
63
24
Downward
J
Control of Ras activation.
Cancer Surv
27
1996
87
25
McCormick
F
Going for the GAPs.
Curr Biol
8
1998
673
26
Ellis
C
Measday
V
Moran
M
Phosphorylation-dependent complexes of p120 Ras-specific GTPase-activating proteins with p62 and p190.
Methods Enzymol
255
1995
179
27
Tocque
B
Delumeau
I
Parker
F
Maurier
F
Multon
MC
Schweighoffer
F
Ras-GTPase activating protein: A putative effector for Ras.
Cell Signal
9
1997
153
28
Zhang
JY
Vik
TA
Ryder
JW
Srour
EF
Jacks
T
Shannon
K
Clapp
DW
NF1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines.
J Exp Med
187
1998
1893
29
Largaespada
DA
Brannan
CI
Jenkins
NA
Copeland
NG
NF1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia.
Nat Genet
12
1996
137
30
Bollag
G
Clapp
DW
Shih
S
Adler
F
Zhang
YY
Thompson
P
Lange
BJ
Freedman
MH
McCormick
F
Jacks
T
Shannon
K
Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.
Nat Genet
12
1996
144
31
Manges
R
Corral
T
Lu
S
Symmans
F
Liu
L
Pellicer
A
NF1 inactivation cooperates with N-Ras in vivo lymphogenesis activating ERK by a mechanism independent of its Ras-GTPase accelerating activity.
Oncogene
17
1998
1705
32
Li
S
Nakamura
S
Hattori
S
Activation of R-Ras GTPase by GTPase-activating proteins for Ras, Gap1 and p120GAP.
J Biol Chem
272
1997
19328
33
Bollag
G
McCormick
F
Identification of a novel ras regulator, a guanine nucleotide dissociation inhibitor.
FASEB J
7
1993
1923
34
Martegani
E
Vanoni
M
Zippel
R
Cloning by functional complementation of a mouse cDNA encoding a homologue of cdc25, a S. cerevisiae ras activator.
EMBO J
11
1992
2151
35
Qian
X
Vass
WC
Papageorge
AG
Anborgh
PH
Lowy
DR
N-terminus of Sos1 Ras exchange factor: Critical role for the Dbl and PH domains.
Mol Cell Biol
18
1998
771
36
Corbalan-Garcia
S
Margarit
SM
Galron
D
Yang
SS
Bar-Sagi
D
Regulation of Sos activity by intermolecular interactions.
Mol Cell Biol
18
1998
880
37
Boriack-Sjodin
PA
Margarit
SM
Bar-Sagi
D
Kuriyan
J
The structural basis of the activation of Ras by Sos.
Nature
394
1998
337
38
Douville
E
Downward
J
EGF-induced Sos phosphorylation in PC12 cells involves p90 RSK2. Ras signalling and apoptosis.
Oncogene
15
1997
373
39
Jefferson
AB
Klippel
A
Williams
LT
Inhibition of mSos activity by binding of PIP2 to the mSos PH domain.
Oncogene
16
1998
2303
40
Lander
HM
Hajjar
DP
Hempstead
BL
Mirza
UA
Chait
BT
Campbell
S
Quilliam
LA
Activation of the receptor for the advanced glycation end products triggers a Ras-dependent MAPK pathway regulated by oxidant stress.
J Biol Chem
272
1997
4323
41
Ebinu
JO
Bottorff
DA
Chan
EY
Stang
SL
Dunn
RJ
Stone
JC
RasGRF, a ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs.
Science
280
1998
1082
42
Gulbins
E
Coggeshall
KM
Baier
G
Katzav
S
Burn
P
Altman
A
Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation.
Science
260
1993
822
43
Bustelo
XR
Suen
KL
Leftheris
K
Meyers
CA
Barbacid
M
Vav cooperates with ras to transform rodent fibroblasts but is not a rasGDP/GTP exchange factor.
Oncogene
8
1994
2405
44
Sturgill
TW
Ray
LB
Erikson
E
Maller
JL
p90 Rsk regulates oestrogen receptor-mediated transcription through phosphorylation of Ser 167.
Nature
334
1998
715
45
Waskiewicz
AJ
Flynn
AF
Pround
CG
Cooper
JA
Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2.
EMBO J
16
1997
1909
46
Wang
X
Flynn
AF
Waskiewicz
AJ
Webb
BL
Vries
RG
Baines
IA
Cooper
JA
Proud
CG
The phosphorylation of the eucaryotic initiation factor IF4E in response to phorbol esters, cell stress and cytokines is mediated by distinct MAP kinase pathway.
J Biol Chem
273
1998
9373
47
Roy
S
Lane
A
Yan
J
McPherson
R
Hancock
JF
Activity of plasma membrane recruited Raf-1 is regulated by Ras via the Raf zinc finger.
J Biol Chem
272
1997
20139
48
Fabian
JR
Vojtek
AB
Cooper
JA
Morrison
DK
A single amino acid change in Raf1 inhibits Ras binding and alters Raf1 function.
Proc Natl Acad Sci USA
91
1994
5982
49
Brtva
TR
Drugan
JK
Ghosh
S
Terrell
RS
Campbell-Burk
S
Bell
RM
Der
CJ
Two distinct Raf domains mediate interaction with Ras.
J Biol Chem
270
1995
9809
50
Li
W
Melnick
M
Perrimon
N
Dual function of Ras in Raf activation.
Development
125
1998
4999
51
Morrison
DK
Cutler
RE
The complexity of Raf regulation.
Curr Opin Cell Biol
9
1997
174
52
Rodriguez-Viciana
P
Warne
PH
Khwaja
A
Marte
BM
Pappin
D
Das
P
Waterfield
MD
Ridley
A
Downward
J
Role of PI3 kinase in cell transformation and control of the actin cytoskeleton by Ras.
Cell
89
1997
457
53
Joneson
T
White
MA
Wigler
MH
Bar
SD
Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of Ras.
Science
271
1996
810
54
Yan
J
Apollini
A
Lane
A
Hankock
JF
Ras isoforms vary in their ability to activate Raf-1 and PI3 kinase.
J Biol Chem
273
1998
24052
55
Ziogas
A
Lorenz
IC
Moelling
K
Radziwill
G
Mitotic Raf is stimulated independently of Ras and is active in the cytoplasm.
J Biol Chem
273
1998
24108
56
Mineo
C
Anderson
RG
White
M
Physical association with Ras enhances activation of membrane-bound Raf (Raf-CAAX).
J Biol Chem
272
1997
10345
57
Stokoe
D
McCormick
F
Activation of Raf-1 by Ras and Src through different mechanisms: Activation in vivo and in vitro.
EMBO J
16
1997
2384
58
Hu
CD
Kariya
K
Kotani
G
Shirouzu
M
Yokoyama
S
Kataoka
T
Coassociation of Rap1A and H-Ras with Raf N-terminal region interferes with Ras-dependent activation of Raf.
J Biol Chem
272
1997
11702
59
York
RD
Yao
H
Dillon
T
Ellig
CL
Eckert
SP
McCleskey
EW
Stork
PJ
Rap1 mediates sustained MAP kinase activation induced by nerve growth factor.
Nature
392
1998
622
60
Katz
M
McCormick
F
Signal transduction from multiple Ras effectors.
Curr Opin Genet Dev
7
1997
75
61
Winkler
DG
Johnson
JC
Cooper
JA
Vojtek
AB
Identification and characterization of mutations in H-Ras that selectively decrease binding to Raf1.
J Biol Chem
272
1997
24402
62
Marte
BM
Downward
J
PKB/Akt. Connecting PI3 kinase to cell survival and beyond.
Trends Biochem Sci
22
1997
355
63
Han
L
Colicelli
J
A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf.
Mol Cell Biol
15
1995
1318
64
Kuriyama
M
Harada
N
Kuroida
S
Yamamoto
T
Nakafuku
M
Iwamatsu
A
Yamamoto
D
Prasad
R
Croce
C
Canaani
E
Kaibuchi
K
Identification of AF6 and canoe as putative targets for Ras.
J Biol Chem
271
1996
607
65
Watari
Y
Kariya
K
Shibatohge
M
Liao
Y
Hu
CD
Goshima
M
Tamada
M
Kikuchi
A
Kataoka
T
Identification of Ce-AF6, a novel C.elegans protein, as a putative Ras effector.
Gene
224
1998
53
66
Freig
LA
Urano
T
Cantor
S
Evidence for Ras/Ral signaling cascade.
Trends Biochem Sci
21
1996
438
67
Vavvas
D
Li
X
Avruch
J
Zhang
XF
Identification of Nore1 as a potential ras effector.
J Biol Chem
273
1998
5439
68
Wolthuis
RMF
Ruiter
ND
Cool
RH
Bos
JL
Stimulation of gene induction and cell growth by the ras effector Rlf.
EMBO J
16
1997
6748
69
Diaz-Meco
MT
Lozano
J
Municio
MM
Berra
E
Frutos
S
Sanz
L
Moscat
J
Evidence for the in vitro and in vivo interaction of Ras with protein kinase C zeta.
J Biol Chem
269
1994
31706
70
Marais
R
Light
Y
Mason
C
Paterson
H
Olson
MF
Marshall
CJ
Requirement of Ras-GTP-Raf complexes for activation of Raf1 by protein kinase C.
Science
280
1998
109
71
Han
L
Wong
D
Dhaka
A
Afar
D
White
M
Xie
W
Herschman
H
Witte
O
Colicelli
J
Protein binding and signaling properties of RIN1 suggest a unique effector function.
Proc Natl Acad Sci USA
94
1997
4954
72
Afar
DE
Han
L
McLaughlin
J
Wong
S
Dhaka
A
Parmar
K
Rosenberg
N
Witte
ON
Colicelli
J
Regulation of the oncogenic activity of BCR/ABL by a tight bound substrate protein Rin1.
Immunity
6
1997
773
73
Wolthuis
RM
Zwartkruis
F
Moen
TC
Bos
JL
Ras-dependent activation of the small GTPase Ral.
Curr Biol
8
1998
471
74
Nimnual
AS
Yatsula
BA
Bar-Sagi
D
Coupling Ras and Rac through the Ras exchange factor Sos.
Science
279
1998
560
75
Adler
V
Pincus
MR
Brandtrauf
PW
Ronai
Z
Complexes of p21ras with Jun N-terminal kinase and Jun proteins.
Proc Natl Acad Sci USA
92
1995
10585
76
Russell
M
Lange-Carter
C
Johnson
GL
Direct interaction between ras and the kinase domain of mitogen activated protein kinase kinase kinase (mekk1).
J Biol Chem
270
1995
11757
77
Chen
CY
Faller
DV
Phosphorylation of Bcl-2 protein and association with p21ras in ras-induced apoptosis.
J Biol Chem
271
1996
2376
78
Rebollo A, Perez-Sasla D, Martinez-A C: Bcl-2 differentially targets K-, N- and H-Ras to mitochondria in IL-2 supplemented cells: Implications in prevention of apoptosis. Oncogene 1999 (in press)
79
Shimizu
K
Kuroda
S
Matsuda
S
Synergistic activation by Ras and 14-3-3 protein of a MAPKKK named Ras-dependent extracellular signal-regulated kinase kinase stimulator.
J Biol Chem
269
1994
31706
80
Therrien
M
Chang
HC
Solomon
N
Karin
FD
Wassarman
DA
Rubin
GM
KSR, a novel protein kinase required for Ras signal transduction.
Cell
83
1995
879
81
Zhang
Y
Yao
B
Delikat
Kinase suppressor of Ras is ceramide-activated protein kinase.
Cell
89
1997
63
82
Stenberg
PW
Alberola-Ila
J
Conspiracy theory: Ras and Raf does not act alone.
Cell
95
1998
447
83
Joneson
T
Fulton
JA
Volle
DJ
Chaika
OV
Bar-Sagi
D
Lewis
R
Kinase suppressor of Ras inhibits the activation of ERK mitogen-activated protein kinase by growth factors, activated Ras and Ras effectors.
J Biol Chem
273
1998
7743
84
Cacace
AM
Michaud
NR
Therrien
M
Mathes
K
Copeland
T
Rubin
GM
Morrison
DK
Identification of constitutive and Ras-inducible phosphorylation sites of KSR: Implications for 14-3-3 binding, MAP kinase binding and KSR overexpression.
Mol Cell Biol
19
1999
229
85
Xing
H
Kornfeld
K
Muslin
AJ
The protein kinase KSR interacts with 14-3-3 protein and Raf.
Curr Biol
7
1997
294
86
Romero
F
Martinez-A
C
Camonis
J
Rebollo
A
Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization.
EMBO J
18
1999
3419
87
Rao
A
Luo
C
Hogan
PG
Transcription factors of the NFAT family: Regulation and function.
Annu Rev Immunol
15
1997
707
88
Woodrow
M
Clipstone
NA
Cantrell
D
p21 and calcineurin synergize to regulate the nuclear factor of activated T cells.
J Exp Med
178
1993
1517
89
Bauerle
PA
Baltimore
D
NF-κB: Ten years after.
Cell
87
1996
13
90
Beg
AA
Baltimore
D
An essential role of NF-κB in prevention of TNFα-induced cell death.
Science
274
1996
782
91
Mayo
MW
Wang
CY
Cogswell
PC
Rogers-Graham
KS
Lowe
SW
Der
J
Baldwin
AS
Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras.
Science
278
1997
1812
92
Finco
TS
Westwick
JK
Norris
JL
Beg
AA
Der
CJ
Baldwin
AS
Oncogenic H-Ras-induced signaling activates NF-κB transcriptional activity, which is required for cellular transformation.
J Biol Chem
272
1997
24113
93
Downward
J
Ras signaling and apoptosis.
Curr Opin Gen Dev
8
1988
49
94
Lavoie
JN
L’Allemain
G
Brunet
A
Muller
R
Pouyssegur
J
Cyclin D1 expression is regulated positively by the p24/p44MAPK and negatively by the p38/HOGMAPK pathway.
J Biol Chem
271
1996
20608
95
Winston
JT
Coats
SR
Wang
YZ
Pledger
WJ
Regulation of the cell cycle machinery by oncogenic Ras.
Oncogene
12
1996
127
96
Arber
N
Sutter
T
Miyake
M
Kahn
SM
Venkatraj
VS
Sobrino
A
Warburton
D
Holt
PR
Weinstein
IB
Increased expression of cyclin D1 and the Rb tumor suppressor gene in K-Ras transformed rat enterocytes.
Oncogene
12
1996
1903
97
Kawada
M
Yamagoe
S
Murakami
Y
Suzuki
K
Mizuno
S
Uehara
Y
Induction of p27kip degradation and anchorage independence by Ras through the MAP kinase signalling pathway.
Oncogene
15
1997
629
98
Atkas
H
Cai
H
Cooper
GM
Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the cdk inhibitor p27kip.
Mol Cell Biol
17
1997
3850
99
Mittnacht
S
Paterson
H
Olson
MF
Marshall
CJ
Ras signalling is required for inactivation of the tumor suppressor pRb.
Curr Biol
7
1997
219
100
Peeper
DS
Upton
TM
Ladha
MH
Neuman
E
Zalvide
J
Bernards
R
DeCaprio
JA
Ewen
ME
Ras signalling linked to the cell cycle machinery by the retinoblastoma protein.
Nature
386
1997
177
101
Graña
X
Reddy
EP
Cell cycle control in mammalian cells: Role of cyclins, cyclin-dependent kinases, growth suppressor genes and cyclin-dependent kinase inhibitors.
Oncogene
11
1995
211
102
Serrano
M
Lian
AW
McCurrach
ME
Beach
D
Lowe
SW
Oncogenic Ras provokes premature senescence associated with accumulation of p53 and p16INK4A.
Cell
88
1997
593
103
Galaktionov
K
Chen
X
Beach
D
Cdc25 cell-cycle phosphatase as a target of c-Myc.
Nature
382
1996
511
104
Conklin
DS
Galaktionov
K
Beach
D
14-3-3 protein associates with cdc25 phosphatases.
Proc Natl Acad Sci USA
92
1995
7892
105
Kerkhoff
E
Rapp
UR
High intensity Raf signals converts mitotic cell cycling into cellular growth.
Cancer Res
58
1998
1636
106
Leone
G
Degregori
J
Sears
R
Jakoi
L
Nevins
JR
Myc and Ras collaborate in inducing accumulation of active cyclin E/cdk2 and E2F.
Nature
387
1997
422
107
Olson
MF
Paterson
HF
Marshall
CJ
Signals from Ras and Rho interact to regulate expression of p21cip.
Nature
394
1998
295
108
Yan
GZ
Ziff
EB
NGF regulates the PC12 cell cycle machinery through specific inhibition of cdk kinases and induction of cyclin D1.
J Neurosci
15
1995
6200
109
Yao
R
Cooper
GM
Regulation of the Ras signaling pathway by GTPase-activating protein in PC12 cells.
Oncogene
11
1995
1607
110
Klese
LJ
Parada
LF
p21 Ras and PI3 kinase are required for survival of wild type and NF1 mutant sensory neurons.
J Neurosci
18
1998
10420
111
Graves
JD
Downward
J
Izquierdo
M
Rayter
S
Warner
PH
Cantrell
DA
The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes.
J Immunol
148
1992
2417
112
Gómez
J
Martı́nez-A
C
Fernández
B
Garcı́a
A
Rebollo
A
Critical role of Ras in proliferation and prevention of apoptosis mediated by IL-2.
J Immunol
157
1996
2272
113
Franke
TF
Kaplan
DR
Cantley
LC
PI3K: Downstream AKTion blocks apoptosis.
Cell
88
1997
435
114
Marte
BM
Rodriguez-Viciana
P
Wennstrom
S
Wartne
PH
Downward
J
PI3 kinase and PKB/Akt act as an effector pathway for R-Ras.
Curr Biol
7
1997
63
115
Cerezo
A
Martinez-A
C
Lanzarot
D
Fischer
S
Franke
T
Rebollo
A
Role of Akt and JNK2 in apoptosis induced by IL-4 deprivation.
Mol Biol Cell
9
1998
3107
116
Kennedy
SG
Wagner
AJ
Conzen
SD
Jordan
J
Bellascosa
A
Tsichlis
PN
Hay
N
The PI3K/Akt signaling pathway delivers an anti-apoptotic signaling.
Genes Dev
11
1997
701
117
Del Peso
L
Gonzalez
M
Page
C
Herrera
R
Nuñez
G
IL-3-induced phosphorylation of BAD through the Akt.
Science
278
1997
687
118
Datt
SR
Dudek
H
Tao
X
Masters
S
Fu
H
Gotoh
Y
Greenberg
ME
Akt phosphorylation of BAD couples cell survival signals to cell-intrinsic death machinery.
Cell
91
1997
23
119
Frisch
SM
Francis
H
Disruption of epithelial cell-matrix interactions induces apoptosis.
J Cell Biol
124
1994
619
120
Khwaja
A
Rodriguez-Viciana
P
Wennstrom
S
Warne
PH
Downward
J
Matrix adhesion and Ras transformation both activate a PI3 kinase and PKB/Akt cell survival pathway.
EMBO J
16
1997
2783
121
Kuribara
R
Kinoshita
T
Miyajima
A
Shinjyo
T
Yoshihara
T
Inukai
T
Ozawa
K
Look
T
Inaba
T
Two distinct IL-3-mediated signal pathways, Ras-NFIL3 and Bcl-x, regulate the survival of murine pro-B lymphocytes.
Mol Cell Biol
19
1999
2754
122
Kinoshita
T
Shirouzu
M
Kamiya
A
Hashimoto
K
Yokoyama
S
Miyajima
A
Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21 Ras in IL-3-dependent hematopoietic cells.
Oncogene
15
1997
619
123
Matin
JL
Baxter
RC
Oncogenic ras causes resistance to the growth inhibitor insulin-like growth factor binding protein-3 in breast cancer cells.
J Biol Chem
274
1999
16407
124
Kinoshita
T
Yokota
T
Arai
K
Miyajima
A
Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells.
Oncogene
10
1995
2207
125
Gómez
J
Martinez-A
C
Gonzalez
A
Garcia
A
Rebollo
A
The Bcl-2 is differentially regulated by IL-2 and IL-4: Role of the transcription factor NFAT.
Oncogene
17
1998
1235
126
Wang
HG
Miyashita
T
Takayama
S
Sato
T
Torigoe
T
Krajewski
S
Tanaka
S
Hovey
L
Troppmair
J
Rapp
UR
Apoptosis regulation by interaction of Bcl-2 protein and Raf-1 kinase.
Oncogene
9
1994
2751
127
Wang
HG
Rapp
UR
Reed
JC
Bcl-2 targets the protein kinase Raf-1 to mitochondria.
Cell
87
1996
629
128
Xia
Z
Dickens
M
Raingeaud
J
Davis
RJ
Greenberg
ME
Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.
Science
270
1995
1326
129
Juo
P
Kuo
CJ
Reynolds
SE
Konz
RF
Raingeaud
J
Davis
RJ
Blenis
J
Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases.
Mol Cell Biol
17
1997
24
130
Lenczwski
JM
Dominguez
L
Eder
AM
King
LB
Zacharchuk
CM
Aswell
JD
Lack of a role for Jun kinase and AP1 in Fas-induced apoptosis.
Mol Cell Biol
17
1997
170
131
Cerezo
A
Martinez-A
C
Gomez
J
Rebollo
A
IL-2 deprivation triggers apoptosis which is mediated by c-Jun N-terminal kinase1 activation and prevented by Bcl-2.
Cell Death Differ
6
1999
87
132
Amar
S
Glozman
A
Chung
D
Adler
V
Ronai
Z
Friedman
FK
Robinson
R
Brandt-Rauf
P
Yamaizumi
Z
Pincus
MR
Selective inhibition of oncogenic Ras in vivo by agents that block its interaction with JNK and Jun protein. Implications for the design of selective chemotherapeutic agents.
Cancer Chemother Pharmacol
41
1997
79
133
Gulbins
E
Bissonnette
R
Mahbouhi
A
Fas-induced apoptosis is mediated via ceramide-initiated Ras signaling pathway.
Immunity
2
1995
34
134
Latinis
KM
Carr
LL
Peterson
EJ
Norian
LA
Eliason
SL
Koretzky
GA
Regulation of Fas ligand expression by TCR-mediated signal events.
J Immunol
158
1997
4602
135
Ferrari
G
Greene
LA
Proliferative inhibition by dominant negative Ras rescues naive and neuronally differentiated PC12 cells from apoptotic death.
EMBO J
13
1994
5922
136
Gómez
J
Martı́nez-A
C
Fernández
B
Garcı́a
A
Rebollo
A
Ras activation leads to cell proliferation or apoptotic cell death upon IL-2 stimulation or lymphokine deprivation, respectively.
Eur J Immunol
27
1997
1610
137
Johnson
L
K-Ras is an essential gene in the mouse with partial functional overlapping with N-Ras.
Genes Dev
11
1997
2468
138
Koera
K
Nakamura
K
Nakao
K
Miyoshi
J
Toyoshima
K
Hatta
T
Otani
H
Aiba
A
Katsuki
M
K-Ras is essential for the development of the mouse embryo.
Oncogene
15
1997
1151
139
Umanoff
H
Edelmann
W
Pellicer
A
Kucherlapati
R
The murine N-Ras gene is not essential for growth and development.
Proc Natl Acad Sci USA
92
1995
1709
140
Pell
S
Divjak
M
Romanowski
P
Impey
H
Hawkins
NJ
Clarke
AR
Hooper
ML
Williamson
DJ
Developmentally-regulated expression of murine K-Ras isoforms.
Oncogene
15
1997
1781
141
Thissen
JA
Gross
JM
Subramanian
K
Meyer
T
Casey
PJ
Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB.
J Biol Chem
272
1997
30362
142
Yan
Z
Deng
X
Chen
M
Xu
Y
Ahram
M
Sloane
BF
Friedman
E
Oncogenic K-Ras, but not oncogenic H-Ras upregulates CEA expression and disrupts basolateral polarity in colon epithelial cells.
J Biol Chem
272
1997
27902
143
Jones
M
Jackson
JH
Ras-GRF activates H-Ras, but not N-Ras or K-Ras4B protein in vivo.
J Biol Chem
273
1998
1782
144
Voice
JK
Klemke
RL
Le
A
Jackson
JH
Four human Ras homologs differ in their abilities to activate Raf-1, induce transformation and stimulate cell motility.
J Biol Chem
274
1999
17164
145
Yan
J
Roy
S
Apolloni
A
Lane
A
Hancock
JF
Ras isoforms vary in their ability to activate Raf-1 and PI3 kinase.
J Biol Chem
273
1998
24052
146
Luo
W
Sharif
M
Stable expression of activated K-Ras does not constitutively activate the MAP kinase pathway but attenuates EFG receptor activation in human astrocytoma cells.
Int J Oncol
14
1999
53
147
Fan
J
Bertino
JR
K-ras modulates the cell cycle via both positive and negative regulatory pathways.
Oncogene
14
1997
2595
148
Liu
M
Lintig
FC
Liyanage
M
Shibata
M
Jorcyk
C
Ried
T
Boss
GR
Green
J
Amplification of K-Ras and elevation of MAP kinase activity during mammary tumor progression in C3SV40 Tag transgenic mice.
Oncogene
18
1998
2403
149
Shibayama
H
Anzai
N
Braun
SE
Fukuda
S
Mantel
C
Broxmeyer
HE
H-Ras is involved in the inside-outsignaling pathway of IL-3-induced integrin activation.
Blood
93
1999
1540
150
Arbiser
JL
Moses
MA
Fernandez
C
Ghiso
N
Cao
Y
Klauber
N
Frank
D
Brownlee
M
Flynn
E
Parangi
S
Byers
HR
Oncogenic H-Ras stimulates tumor angiogenesis by two distinct pathways.
Proc Natl Acad Sci USA
94
1997
861
151
Matsuguchi
T
Kraft
AS
Regulation of myeloid cell growth by distinct effectors of Ras.
Oncogene
17
1998
2207
152
Shin
DY
Ishibashi
T
Choi
TS
Chung
E
Chung
Y
Aaronson
S
Bottaro
DP
A novel human ERK phosphatase regulates H-Ras signal transduction.
Oncogene
14
1997
2633
153
Maher
J
Baker
DA
Manning
M
Dibb
NJ
Roberts
IAG
Evidence for cell-specific differences in transformation by N-, H- and K-Ras.
Oncogene
11
1995
1639
154
Hamilton
M
Wolfman
A
H-Ras and N-Ras regulate MAPK activity by distinct mechanisms in vivo.
Oncogene
16
1998
1417
155
Miyauchi
J
Asada
M
Sasaki
M
Tsuneamatsu
Y
Kojima
S
Mizutani
S
Mutations of the N-Ras gene in juvenile chronic myelogenous leukemia.
Blood
83
1994
2248
156
Kiyoi
H
Naoe
T
Nakano
Y
Yokota
S
Minami
S
Miyawaki
S
Asou
N
Kuriyama
K
Jinnai
I
Shimazaki
C
Akiyama
H
Saito
K
Motoji
T
Omoto
E
Saito
H
Ohno
R
Ueda
R
Prognostic implication of FLT3 and H-Ras gene mutations in acute myeloid leukemia.
Blood
93
1999
3074
157
MacKenzie
KL
Dolnikov
A
Millington
M
Shounan
Y
Symonds
G
Mutant N-ras induces myeloproliferative disorders and apoptosis in bone marrow repopulated mice.
Blood
93
1999
2043
158
Darley
RL
Hoy
TG
Baines
P
Padua
RA
Burnett
AK
Mutant N-Ras induces erythroid lineage dysplasia in human CD34+ cells.
J Exp Med
185
1999
1337
159
Okumura
K
Shirasawa
S
Nishioka
M
Sasazuki
T
Activated K-Ras suppresses 12-O-tetradecanoylphorbol-13-acetate induced activation of the c-jun NH2-terminal kinase pathway in human colon cancer cells.
Cancer Res
59
1999
2445

Author notes

Address reprint requests to Angelita Rebollo, Centro Nacional de Biotecnologı́a, Department of Immunology and Oncology, Universidad Autónoma, Campus de Cantoblanco, E-28049 Madrid, Spain; e-mail: arebollo@cnb.uam.es.

Sign in via your Institution