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Cell Growth & Differentiation Vol. 12, 397-408, August 2001
© 2001 American Association for Cancer Research

Review

Molecular Mechanisms Mediating Mammalian Mitogen-activated Protein Kinase (MAPK) Kinase (MEK)-MAPK Cell Survival Signals1

Bryan A. Ballif and John Blenis2

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115


   Introduction
TOP
 Introduction
Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
 RSK Family Members Link...
 RSK Family Members Phosphorylate...
 PKA Cooperates with MAPK...
 MEK-dependent Survival May Be...
 Defining the Role of...
 References
 
To maximize advantages and reduce costs associated with life as an interdependent community of cells, multicellular organisms have evolved common mechanisms to regulate the life and death of their individual cells. Critical to the health and survival of a multicellular organism is its ability to selectively sustain advantageous cells and selectively eliminate cells that threaten the survival of its cellular community. Therefore, regulated survival of individual cells evolved in a manner consistent with organismal and population survival priorities. The molecular signaling mechanisms that drive these life and death decisions have been the subject of intense research. This is because of their primary role in tissue development and maintenance and in the number of pathological states that may develop when such signaling goes awry. Excessive cell survival can lead to disorders such as cancer and autoimmunity, and insufficient cell survival can lead to tissue degenerative and developmental disorders.

Efficient removal of cells that are damaged, malignant, or otherwise organismally threatening occurs by selectively triggering latent "self-destruction" machinery present in each cell. This regulated cell death can be triggered rapidly (death within 2–8 h) by activation of extracellular cell death receptors (see Refs. 1, 2, 3 for reviews on death receptor-mediated cell death). The union of a death ligand with its receptor initiates the assembly of a signaling complex around the cytoplasmic tail of the receptor. This complex recruits and activates cysteine proteases (caspases), the proteolytic activity of which leads to the demise of the cell (see Refs. 4 and 5 ) for reviews on caspases). Alternatively, cell death can be triggered by a relatively slow mechanism (roughly 8 h to 2 days) by removing the survival signals that normally sustain cells, keeping the cell death machinery at bay. This slower form of death appears to be primarily dependent on the regulation of mitochondrial integrity and/or function through modulation of Bcl-2 family members (see Refs. 6, 7, 8, 9, 10 for reviews on the Bcl-2 family). Loss of mitochondrial integrity leads to the release of agents such as cytochrome c and apoptosis-inducing factor that can lead to caspase-dependent or caspase-independent cell death, respectively (see Refs. 11, 12, 13, 14, 15, 16 for reviews on mitochondria and cell death).

Multicellular organisms produce a host of secreted and cell-tethered survival factors that cooperate with metabolic precursors to sustain the life of responsive tissues. Many cell types survive less than 12 h without constant support provided by survival factors. The molecular mechanisms whereby survival factors exert their effects are only beginning to be unraveled. The best understood and perhaps primary role of cell survival factors is to mobilize signaling molecules that ultimately protect the integrity of mitochondria (the focus of this review). However, in some cell types, these signaling cascades may also antagonize death induced by activated death receptors (17, 18, 19, 20, 21) . The most dynamic players in cell survival signaling cascades are now being revealed and characterized. However, the regulatory complexity found in each cascade is not trivial. Multiple cascades can be simultaneously activated by one survival factor and a combination of survival factors can provide synergistic support. Additionally, differences in the expression levels of the receptors for specific survival factors can significantly alter the signal strength and final outcome of a given survival factor. It is thus challenging to evaluate the effect of the activity of one signaling pathway in isolation. Nevertheless, the molecular events propagated by distinct signaling pathways are currently emerging, revealing their economical use and synergistic targeting of common effector substrates. Fig. 1Citation shows the convergence of three core signaling pathways on two common effector substrates, the proapoptotic Bcl-2 family member, BAD, and the transcription factor CREB.3 In addition to the survival pathways shown in Fig. 1Citation , several others have been identified. This review, however, will focus on the molecular mechanisms of mammalian cell survival mediated by canonical MAPK signaling. MAPK-dependent cell survival mechanisms have also been described in Drosophila (22 , 23) , but because these pathways have yet to show conservation in mammals, they will not be discussed here.



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  		Fig. 1. Core kinase cascades transduce survival signals that converge on common effector substrates and regulate mitochondrial integrity. Survival factors such as IL-3 and BDNF can activate signaling pathways capable of relaying their molecular instructions to the cell death machinery via kinase cascades. Depicted here are three core cell survival signaling cassettes converging on two common effector substrates. PI 3-K-Akt, MEK-ERK-RSK, and cyclic AMP-PKA pathways can control the cell death machinery by neutralizing the pro-apoptotic effects of BAD and by up-regulating the transcriptional activity of CREB. Phosphorylated BAD is kept in the cytosol by 14-3-3 proteins and thus is impaired in its ability to antagonize the mitochondrial-protective functions of a number of Bcl-2 family members. Activated CREB can positively influence the transcription of pro-survival genes including the Bcl-2 family members, Bcl-2, Bcl-XL, and Mcl-1, and survival factors such as BDNF. PD 098059 and U0126 are chemical inhibitors of MEK activation and LY294002 and wortmannin are direct inhibitors of PI 3-K (see text for details).

 
The classical MAPKs or ERKs 1 and 2 are activated by MEKs 1 and 2 (24) . MEK1/2-ERK1/2 signaling plays a critical role in the cell survival of a number of cell types. Herein the evidence for the involvement of ERKs in cell survival and the strengths and limitations of each research tool used in forming such conclusions will be discussed. Particular emphasis will be placed on the contexts in which ERK signaling plays a primary or strong supporting role and the recent advances made in connecting ERK signals to the cell death machinery.


   Molecular Pharmacology Provides Evidence for MEK-dependent Cell Survival Signaling
TOP
 Introduction
 Molecular Pharmacology Provides...
Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
 RSK Family Members Link...
 RSK Family Members Phosphorylate...
 PKA Cooperates with MAPK...
 MEK-dependent Survival May Be...
 Defining the Role of...
 References
 
The capacity of defined small molecules to penetrate the cell and selectively perturb the activity of specific signaling proteins has proven an invaluable tool in delineating signal transduction pathways and the cellular processes they control. A particular strength of such tools is their ability to inhibit cellular levels of the target molecule in a short time course. There is no requirement for exogenous overexpression, and signaling pathways have little time to develop new circuitry to circumvent the action of the drug. Thus, any compensatory effects induced by the drug are likely minimal compared with certain alternative approaches including targeted gene disruption through classical homologous recombination techniques. Such techniques can place the developing embryo under significant selection pressure to rewire its signaling networks and thereby complicate the analysis.

The recently reported MEK inhibitors, PD 098059 (25 , 26) and U0126 (27) , have by far been the most widely used tools to show MEK dependency in cell survival. However, to evaluate the effect of these drugs on cell survival, it is imperative to understand the molecular basis of their inhibition and the manner in which the drugs are used. Both inhibitors prevent the full activation of MEK1/2 without competing with ATP or substrate. However, the degree to which these drugs are effective is a function of the states of MEK1/2 activation (Table 1)Citation . The basal activity of MEK1/2 (and its ability to be activated by purified Raf) is strongly inhibited by either drug in vitro. In great contrast, activated MEK1/2 isolated from stimulated cells or activated in vitro with recombinant Raf is almost entirely resistant to PD 098059 and an order of magnitude more resistant to U0126 (Table 1)Citation . Surprisingly, activated alleles of MEK1/2, with activation loops harboring phospho-acceptor serine residues mutated to acidic residues (for MEK1–S217E, S221E) remain largely sensitive to the inhibitors. This is likely functionally related to their relative specific activities, as well as an indication that acidic residues do not always functionally mimic phosphate groups. MEK1-S217E, S221E (MEK1-EE) is roughly 40 times more active than unphosphorylated MEK1 but 180-fold less active than fully phosphorylated MEK1 (25) . Thus, the relative resistance of active MEK1/2 to PD 098059 and U0126 raises the first of a number of potential pitfalls when using these inhibitors to argue for or against MEK1/2 in cell survival signaling (Table 2)Citation :


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  		Table 1 The IC50 of PD 098059 and U0126 for in vitro inhibition of MEK family members in different activation states

 

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  		Table 2 Pharmacological pitfalls leading to misinterpretations in survival signaling

 
(a) If these inhibitors (most particularly PD 098059) are added to cells without initially starving the cells of survival factors and thereby inactivating MEK1/2, the effects of the drugs may never be observed. This may then lead to a potentially inappropriate dismissal of MEK1/2 as an important component of the survival signal.

(b) As with any drug, the specificity for the understood target is paramount to a full interpretation of its effects. Thus, a constant pharmacological concern is what additional effects a particular drug may exert on all of the other molecules in the cell. Although PD 098059 can prevent the activation of MEK1/2, it can also hyperactivate Raf (25) . Recently, PD 098059 and U0126 were also shown to inhibit MEK5 (Ref. 28 and Table 1Citation ). MEK5 can be activated by Ras, and it directly activates ERK5 or Big MAPK1 (BMK1; Ref. 28 ). Thus, in addition to classical MEK-MAPK signaling, one must consider the newly identified MEK5-ERK5 signaling cassette when evaluating PD 098059 and U0126 in cell survival signaling.

(c) [a sub-pitfall of (b)], cross-talk between core signaling pathways can be cell type and survival factor specific. Cross-talk between PI 3-K and ERKs are of particular relevance (29) . Perhaps the primary and most defined survival signaling cascade in many cell types involves PI 3-K and its downstream target Akt or protein kinase B (30 , 31) . Similar to the pharmacological inhibitors of MEK isoforms, the inhibitors of PI 3-K, LY294002 and wortmannin, antagonize the action of a number of survival factors. Given the important protective function of Akt, cell death evoked by LY294002 or wortmannin is understandably and in many cases appropriately attributed to the loss of Akt activity. However, Akt is certainly not the only PI 3-K-activated molecule involved in cell survival. Among others, PI 3-K can activate survival kinases such as serum and glucocorticoid regulated kinase (SGK; Refs. 32 and 33 ) and certain protein kinase C family members (34) . In addition, critical to the activation of a number of kinases with homology to protein kinase C, including Akt and the ERK-activated, 90 kDa RSK, is PDK1 (35, 36, 37, 38) . Although PDK1 kinase activity appears largely unaffected by PI 3-K activity, PDK1 contains a pleckstrin homology domain capable of binding PI 3-K lipid products and thereby altering the cellular localization of PDK1 (35) . Thus, inhibition of PI 3-K activity could disrupt spatial regulation of PDK1 and thereby potentially diminish Akt- and RSK-mediated survival signaling (see below).

Cross-talk between PI 3-K signaling and Ras-Raf signaling can be dramatically different, depending on the agonist and cellular context. PI 3-K activity down-regulates Raf signaling in some contexts (39, 40, 41) and is required for Ras and Raf signaling in other contexts (Fig. 1Citation , dotted lines; Refs. 42, 43, 44, 45 ). It is therefore inappropriate to exclude MEK-ERK-dependent signals solely on the basis that cellular survival is entirely sensitive to PI 3-K inhibitors. Differential sensitivity of ERK1/2 to PI 3-K inhibitors is exemplified in Fig. 2Citation . In Swiss 3T3 cells, the activation of ERKs and RSK by insulin is sensitive to PI 3-K inhibition. In human embryonic kidney (HEK) 293 cells, the activation of ERKs and RSK by EGF is independent of PI 3-K activity (Fig. 2)Citation . Yet in the same cells, the activation of ERKs and RSK is dependent on PI 3-K activity when serum is the stimulus (not shown).4 Akt activation remains sensitive to wortmannin independent of these agonists and cell types (Fig. 2Citation and data not shown). One reason for the differential dependency of ERK on PI 3-K appears to be the strength of the stimulus, which can be proportional to the number of activated receptors (46) . Temporal concerns must also be considered when determining the effect of cross-talk. The prolonged activation of ERKs in Swiss 3T3 cells stimulated with platelet-derived growth factor is partially dependent on PI 3-K, whereas the initial burst of activation is not (47) . Such complexities underscore the danger in assuming simple linearity in signal transduction pathways and emphasize the need to be cognizant of the several pathways that may be acting in concert.



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  		Fig. 2. ERK1/2 and RSK activation is differentially sensitive to PI 3-K inhibition. Swiss 3T3 and HEK 293E cells were starved of serum for 24 h, pretreated for 30 min with 100 nM wortmannin where indicated, and stimulated for 10 min with either 100 nM insulin or 25 ng/ml EGF as indicated. Cell lysates were then subjected to either immunoblotting with the indicated antibodies or immunoprecipitation kinase reactions using GST-BAD as substrate (see Refs. 38 and 51 for further details on experimental procedures).

 

   Activated Alleles of MEK1/2 Promote Cell Survival Independently of Survival Factors
TOP
 Introduction
 Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
Dominant Interfering MEK1/2...
 RSK Family Members Link...
 RSK Family Members Phosphorylate...
 PKA Cooperates with MAPK...
 MEK-dependent Survival May Be...
 Defining the Role of...
 References
 
Notwithstanding the ability of Ras to sensitize some cells to cell death, Ras is a critical mediator of cell survival in many cell types (48) . Initial studies dissecting the multiplicity of Ras-dependent survival signals used effector domain mutants of activated Ras that were incapable of activating either PI 3-K or Raf (49 , 50) . These studies showed that Ras-dependent survival could be dependent on signals transduced by both PI 3-K and Raf. These reports were followed by many similar results using activated alleles of Raf and MEK1/2 (Table 3)Citation Citation . The strength of such studies lies in their ability to examine the effect of individual signaling molecules in the absence of survival factors. A potential limitation of this approach is the reliance on the overexpression of the mutant construct. High expression levels may not accurately reflect the endogenous signal strength (and perhaps circuitry) seen in primary tissues. In addition, the evaluation of their effects may occur as many as 2 days after their introduction in transient assays. Given this length of time, secondary effects or autocrine/paracrine loops may evoke additional signaling cascades and thus add to the complexity of the final analysis. Nonetheless, naturally occurring examples of such expression may be found in transformed tissues, which typically show up-regulated expression levels of activated signaling molecules. In addition, autocrine/paracrine loops may play integral roles in promoting such disease states.


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  		Table 3 Evidence for MEK-dependent survival in a variety of cell types and initiated by numerous stimuli

 

   Dominant Interfering MEK1/2 Alleles Disrupt Cell Survival Signaling
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 Introduction
 Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
RSK Family Members Link...
 RSK Family Members Phosphorylate...
 PKA Cooperates with MAPK...
 MEK-dependent Survival May Be...
 Defining the Role of...
 References
 
A companion approach to the one mentioned above is the use of dominant interfering mutants of MEK1/2. Experiments introducing these alleles into cells have resulted in inhibition of survival signaling in a number of cell types (Table 3)Citation . An anti-survival effect seen by disrupting potentially only one signaling molecule (when multiple signaling pathways may be engaged) underscores the inability of another signaling pathway to fully compensate for the insult. Depending on the efficacy of interference, the degree to which survival is lost may correlate with the relative dependency the survival factor has on this molecule (and its downstream targets).

An additional strength in these studies is that dominant interfering mutants theoretically disrupt the activation of their endogenous counterparts and do not rely on the overexpression of catalytically active components of the pathway. The dominant negative effect is most easily explained by the titration of upstream activators away from the endogenous target. However, this approach can be complicated by the potential of such a titration affecting upstream activators common to multiple pathways. Ultimately, data from multiple approaches finally yield a more clear understanding of "normal" cellular events.


   RSK Family Members Link MEK1/2-dependent Survival Signals to the Cell Death Machinery
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 Introduction
 Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
 RSK Family Members Link...
RSK Family Members Phosphorylate...
 PKA Cooperates with MAPK...
 MEK-dependent Survival May Be...
 Defining the Role of...
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Whereas significant evidence had been generated for MEK-dependent survival signals, the molecular route from MEK1/2 through ERK1/2 to the suppression of the cell death machinery remained to be traversed. Three reports have now emerged showing the promotion of cell survival by members of the ERK-activated, RSK family of serine/threonine kinases (51, 52, 53) . Dominant-negative RSK alleles were shown to eliminate survival afforded by activated MEK alleles (51 , 52) and to antagonize survival mediated by the survival factors BDNF (52) and IL-3.5 In addition to dominant-negative data, a novel activated RSK1 allele was used that contained an NH2-terminal myristoylation signal, presumably relieving spatial and/or structural constraints, thus providing unregulated activation by PDK1. In the absence of survival agonists, this allele afforded survival equivalent to the levels obtained with activated MEK (51) .

These reports did not simply add another kinase to the survival cascade but additionally elucidated a mechanism linking MEK-dependent signals directly to the cell death machinery. Significant insight into potential mechanisms whereby kinases could influence the cell death machinery came from studies showing PI 3-K-dependent Akt phosphorylation of the proapoptotic Bcl-2 family member, BAD (54 , 55) . Phosphorylation of BAD at S136 by Akt was shown to reduce its interference with the pro-survival Bcl-2 family member Bcl-XL and increase the affinity of BAD for cytosolic 14-3-3 proteins (54 , 56) . With BAD relegated to the cytosol, it could no longer antagonize the pro-survival function of Bcl-XL. Earlier work showed mitogen-regulated phosphorylation of BAD at both S112 and S136 (56) , with the phosphorylation of S136 being sensitive to PI 3-K inhibitors (54) and the phosphorylation of S112 being sensitive to MEK inhibitors (57 , 58) . MEK-dependent phosphorylation of BAD was also shown to disrupt the amount of endogenous BAD that interacted with endogenous Bcl-2 (58) . However, the MEK-dependent, BAD kinase(s) had not been identified.

The three reports mentioned above all showed RSK-dependent phosphorylation of BAD at S112 by in vitro kinase assays (51, 52, 53) . Overexpression of wild-type RSK in cells could likewise enhance phosphorylation of BAD at S112 (52 , 53) , and overexpression of myristylated RSK showed constitutive BAD S112 phosphorylation in the absence of survival factors and mitogens (51) . Conversely, the expression of dominant interfering mutants of RSK antagonized S112 phosphorylation of BAD (51 , 52) . Consistent with previous reports showing that BAD S112 phosphorylation was important for its interaction with 14-3-3 proteins, RSK-induced BAD phosphorylation enhanced its ability to bind 14-3-3 proteins {epsilon} and {delta} (53) . Taken together, these data provided strong evidence for the first linear molecular pathway linking MEK-ERK survival signals to the cell death machinery via RSK.


   RSK Family Members Phosphorylate CREB and Elicit Transcription of Pro-Survival Proteins
TOP
 Introduction
 Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
 RSK Family Members Link...
 RSK Family Members Phosphorylate...
PKA Cooperates with MAPK...
 MEK-dependent Survival May Be...
 Defining the Role of...
 References
 
In addition to the rapid, posttranslational modification of BAD by RSK, accumulating evidence suggested that another known RSK target, the transcription factor CREB, played a critical role in cell survival. A CREB allele harboring a S133A mutation that could not be regulated by RSK activity antagonized the action of a number of survival factors (52 , 59 , 60) . The relatively slower mechanism of protection by regulating transcription may be the result of increasing the transcription of pro-survival proteins or interfering with the transcription of pro-death proteins. To date, there is primarily only evidence to support the former when considering CREB phosphorylation at serine 133. Serine 133 phosphorylation of CREB can lead to the MEK-dependent transcriptional up-regulation of the pro-survival Bcl-2 family members Bcl-2, Bcl-XL, and Mcl-1 (61, 62, 63, 64, 65, 66, 67, 68) and to increased expression of the survival factor BDNF (Refs. 60 and 69 ; Fig. 1Citation ).

Of great interest and particular relevance to MEK-dependent CREB signaling is a recently identified class of RSK family members called MSKs. MSK1 [also RSK-like protein kinase (RLPK); Refs. 70 and 71 )] and MSK2 (also RSK-B; Refs. 70 and 72 ) are distinct from classical RSK family members in three primary ways: (a) they can be activated by not only ERK1/2 but by the stress MAPK, p38 (70, 71, 72) ; (b) notwithstanding their nearly identical activation loops, MSK1, but not RSK, can be activated in PDK1-/- embryonic stem cells in response to phorbol esters (73) . This implies that not PDK1 but a related unidentified kinase is required to phosphorylate the activation loop of MSK1; and (c) MSKs are constitutively located in the nucleus (70, 71, 72) , whereas RSK localization appears to be largely cytosolic, with increased nuclear localization in response to mitogens (74) . Targeted disruption of MSK1 in embryonic stem cells resulted in a significant reduction in MEK-dependent CREB serine 133 phosphorylation in response to phorbol esters and EGF (75) . Interestingly, this drop in phorbol ester-induced CREB phosphorylation was the least dramatic at short induction times (10 min; Ref. 75 ). This points a finger at MSK1 as a prime candidate for sustained MEK-dependent CREB phosphorylation and may suggest (without knowing the contribution of MSK2) that classical RSK family members provide a more rapid, and possibly transient, CREB phosphorylation. However, the individual roles of RSK family members in CREB phosphorylation are likely to depend on the stimulus and cellular context. To further address this issue, it will also be important to determine whether CREB phosphorylation is reduced in cells lacking PDK1 (73) or when PDK1 signaling is disrupted pharmacologically (38) and whether MSK deficiencies result in decreased cell survival.


   PKA Cooperates with MAPK and PI 3-K to Mediate Cell Survival
TOP
 Introduction
 Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
 RSK Family Members Link...
 RSK Family Members Phosphorylate...
 PKA Cooperates with MAPK...
MEK-dependent Survival May Be...
 Defining the Role of...
 References
 
The cyclic AMP-dependent PKA is activated by a number of survival factors. Similar to its relatives RSK and Akt, PKA is another player in the cell’s repertoire of kinases able to modulate the activity of BAD and CREB (Fig. 1)Citation . PKA has long been known to mediate serine 133 phosphorylation of CREB (76) , and has been shown recently to anchor to the mitochondrial membrane (77) and phosphorylate BAD at serine 155 (78, 79, 80) . Serine 155 phosphorylation of BAD dramatically reduces the ability of BAD to induce death. Serine 155 phosphorylation occurs in the Bcl-2 homology 3 (BH3) domain of BAD, and this phosphorylation may prevent BAD from inserting into the mitochondrial membrane (81) and thereby antagonize its interference with pro-survival Bcl-2 family members (82) . BAD species that are phosphorylated at serine 155 and dissociated from the mitochondria may thus be further spatially exposed to regulation by cytosolic kinases such as RSK and Akt. RSK phosphorylation of BAD at serine 112 and Akt phosphorylation of BAD at serine 136 may increase the avidity of the binding of 14-3-3 isoforms to BAD. Interestingly, 14-3-3 binding to BAD appears to facilitate its phosphorylation by PKA (80) . However, the presence of PKA activity in the absence of Akt and RSK activity may be insufficient to maintain survival in some cells. Pharmacological disruption of PDK1 signaling prevents the activation of RSK and Akt with no apparent loss of PKA activity. This results in reduced BAD phosphorylation and cell death in IL-3-dependent 32D cells (38) . It is fascinating that phosphorylation of one site (serine 133) in CREB may be mediated by the activation of MEK, PI 3-K, and PKA (68 , 76 , 83 , 84) , whereas these same pathways lead to the phosphorylation of distinct sites in BAD (serines 112, 136, and 155, respectively). This shows two unique mechanisms whereby evolution has harnessed signal transduction pathways for the maintenance of cell survival.


   MEK-dependent Survival May Be Independent of MEK-dependent Proliferation
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 Introduction
 Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
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Not surprisingly, cells selected for survival may also be selected for proliferation. The mechanisms that promote cell survival and those that drive cell proliferation can be integrally connected. Indeed, survival factors often double as proliferation factors. This tangle makes a clean distinction between proliferation and survival tricky. The analysis is further complicated in rapidly dividing cells because proliferation stimuli and survival stimuli appear to be not only transduced by similar sets of signaling pathways but appear to regulate the transcription of similar sets of genes (85) . However, nonproliferating or slowly differentiating cells require signals promoting survival; yet these signals do not drive cell cycle progression. What then are the distinct differences between signals inducing proliferation and signals promoting survival? Are such differences entirely unique to a particular cell type and survival factor, or do survival signals evoke common mechanisms independent of cell type and which are distinct from proliferation? If such discrete mechanisms exist, how are they executed?

These questions are the topic of a number of current studies. One way to achieve such a difference could be the duration of the signal. A number of reports have identified factors that lead to either a prolonged or transient activation of ERKs (85 , 86) . Depending on the cell type, the duration of ERK signaling (and/or the modulation of its downstream targets) has correlated with various biological outcomes (86) . Prolonged activation of ERKs leads to sustained CREB phosphorylation and differentiation in PC12 cells, cyclin D1 expression and cell cycle progression in fibroblasts, prolonged CREB phosphorylation and cell survival of Schwann cells (60 , 85, 86, 87) , and c-fos stabilization and cell cycle progression in Swiss 3T3 cells.6 Although the strength of the initial signal appears critical to obtain prolonged ERK activation (46 , 88) , a number of molecular details await further elucidation.


   Defining the Role of MEK-MAPK Signaling in Genetic Systems Is a Promising Yet Challenging Endeavor
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Given the interconnected nature of cell survival, proliferation, and differentiation, it is difficult to evaluate cell survival as a unique mechanism, particularly in an organismal setting. For example, would the phenotype attributable to the lack of one RSK family member (see below) be the result of a defect in proliferation, differentiation, or cell survival or a combination of the three? This task is further complicated by redundancy in the genes encoding mammalian MEK-MAPK signaling molecules. As mentioned above, mammals have three MEK family members (MEK1/2/5), three ERK family members (ERK1/2/5), and six RSK family members (RSK1–4 and MSK1/2). Notwithstanding the relative paucity of genetic data regarding mammalian MEK-MAPK signaling, genetic deficiencies in the MEK, ERK, or RSK signaling molecules are revealing fascinating phenotypes.

The critical role of MEK1 in mammalian organismal survival is evident in that targeted deletion of MEK1 in mice is lethal at embryonic day 10.5. This appears to be attributable to their failure to generate or maintain placental vasculature (89) . In addition, fibroblasts from MEK1-deficient embryos exhibit migration defects (89) . Targeted disruption of ERK1 results in mice with thymocyte maturation defects (90) , and the disruption of RSK2 leads to a smaller and shorter mouse that has defects in learning, coordination, and glycogen metabolism (91) . This latter phenotype suggests that RSK2 plays a role in proper neurological activity and is consistent with RSK2 deficiencies being the primary cause of the human genetic and mental retardation disorder, Coffin-Lowry syndrome (92 , 93) . Another X-linked mental retardation disorder is linked to RSK4 (94) , and MSK2 (RSK-B) is located in an approximately 1-Mb region associated with Bardet-Biedl syndrome I, which has associated mental retardation manifestations (95, 96, 97) .

It is too early to tell whether such genetic disruptions of MEK-dependent signaling directly reflect reduced cell survival. However, cell culture studies predict that loss of MEK-ERK-RSK signaling will result in a reduction of those cell types that require their activity (Table 3)Citation . The degree to which such alterations become significant may heavily depend on the relative expression levels of the various MEK-ERK-RSK family members in any given cell.

Notwithstanding the diversity of complex signaling cascades and the numerous survival factors that trigger them, emerging tools in cell biology have provided strong evidence supporting a distinct role for the MEK-ERK signaling cassette in cell survival. Over the last decade, MEK-dependent survival has been established in diverse types of primary cells and established cell lines (Table 3)Citation . However, only in recent years has evidence traced mammalian MEK-dependent signals directly to the regulation of the cell death machinery. These recent reports describe the ability of RSK family members to phosphorylate BAD and CREB and thereby transduce MEK-dependent signals into the maintenance of mitochondrial integrity. This webbed regulatory control provided by the convergence of multiple signaling pathways, described for only two such effector substrates, may imply that the cell has yet to reveal more of such commonalities and complexities.

These new molecular descriptions of MEK-dependent cell survival reveal phenomenal conservation in the cell’s use of critical regulatory mechanisms by various cell survival signaling cassettes. These cassettes are activated by a vast array of survival factors and subsequent mobilization of diverse second messengers. Yet, many of these signaling pathways lead to the activation of kinases of similar substrate specificity that can converge on common effector substrates and generate similar cellular outcomes. The evolution of such breadth in signaling potential affords multicellular organisms great regulatory control over the life and death of their individual cells, thereby promoting the survival of both the organism and the species.


   Acknowledgments
 
We thank A. Shimamura and L. Murphy for critical reading of the manuscript and A. Shimamura, L. Murphy, and S. Richards for sharing unpublished data. Because this review covers data generated by a large number of laboratories, we acknowledge the many investigators that have contributed to this field. Although we have endeavored to be complete, we regret any oversight preventing proper acknowledgment.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by Grants CA45695 and GM51405 from the NIH and a Hoechst Marion Roussel Exploratory award. Back

2 To whom requests for reprints should be addressed, at Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115. Phone: (617) 432-4848; Fax: (617) 432-1144; E-mail: jblenis{at}hms.harvard.edu Back

3 The abbreviations used are: CREB, cyclic adenosine monophosphate response element binding protein; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; ERK, extracellular regulated kinase; PI 3-K, phosphatidylinositide 3-kinase; RSK, ribosomal S6 kinase; PDK, 3-phosphoinositide-dependent kinase; EGF, epidermal growth factor; BDNF, brain-derived neurotrophic factor; IL, interleukin; MSK, mitogen- and stress-activated kinase; PKA, protein kinase A. Back

4 S. Richards and J. Blenis, unpublished observations. Back

5 A. Shimamura and J. Blenis, unpublished results. Back

6 L. Murphy and J. Blenis, unpublished results. Back

Received for publication 4/27/01. Accepted for publication 5/ 8/01.


   References
TOP
 Introduction
 Molecular Pharmacology Provides...
 Activated Alleles of MEK1/2...
 Dominant Interfering MEK1/2...
 RSK Family Members Link...
 RSK Family Members Phosphorylate...
 PKA Cooperates with MAPK...
 MEK-dependent Survival May Be...
 Defining the Role of...
 References
 

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