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The roles of mammalian mitogen-activated protein kinase-activating protein kinases (MAPKAPKs) in cell cycle control


Sergiy Kostenko, Alexey Shiryaev, Nancy Gerits, Ugo Moens*




University of Tromsø, Faculty of Medicine, Institute of Medical Biology, Department of Microbiology and Virology, N-9037 Tromsø, Norway.



*corresponding author: Ugo Moens, University of Tromsø, Faculty of Medicine, Institute of Medical Biology, Department of Microbiology and Virology, N-9037 Tromsø, Norway. Phone: +47-77644622, fax: +47-77645350, e-mail: ugom@fagmed.uit.no



Key words: MAPK-activated protein kinase, p53, cyclin-dependent kinase, Cdc25, multicellular organism, oocytes, MAPK inhibitors.

Summary


Signal transduction pathways often modulate cell proliferation by targeting the activity of cell cycle regulating proteins. One of the signaling pathways that can control the cell cycle is the mitogen-activated protein kinase (MAPK) signaling cascade. In mammalian cells, the classical MAPK pathway consists of sequential phosphorylation events leading to activation of a MAPK kinase kinase, a MAPK kinase, and a MAPK. MAPK in turn phosphorylates non-protein kinase substrates such as transcription factors, but it can also phosphorylate yet other protein kinases, referred to as MAPK-activating protein kinases (MAPKAPK). Eleven mammalian MAPKAPKs have been identified so far; six of them belong to the group of AGC protein kinases (RSK1, RSK2, RSK3, RSK4, MSK1, and MSK2), while the other five belong to the family of calmodulin-dependent kinases (MK2, MK3, MK5, MNK1, and MNK2). In this review we will discuss those MAPKAPKs that play a role cell-cycle regulation as well as the potential use of specific MAPKAPK inhibitors as therapy in conditions with abnormal cell cycle regulation.

1. The cell cycle

The cell cycle in somatic cells of multicellular organisms is a complex process that consists of four successive stages: the G1, S, G2 and M phase (Figure 1). During the G1 (gap) phase, the cell prepares for DNA replication, while DNA replication itself occurs in the S (synthesis) phase. After the S phase, cells are stalled in a second gap phase (G2), during which the replicated DNA is checked for mistakes and, if necessary repaired before it is passed on to the daughter cells. The replicated chromosomes are separated during the M (mitosis) phase, after which two daughter cells arise. These can, in turn re-enter the cell cycle [reviewed in Morgan, 2007]. In gametocytes, the mitosis phase is replaced by meiosis, which can be subdivided in meiosis I and meiosis II [Marston and Amon, 2004; Pawlowski and Cande, 2005; van den Heuvel, 2005].Quiescent cells that no longer divide enter a so-called G0 phase [reviewed in Morgan, 2007].



Figure 1. Simplified presentation of the cell cycle in somatic cells. The cell cycle can be divided in 4 successive phases: G1, S, M and G2. Non-dividing cells enter the G0 phase. Complexes of cyclin/Cyclin-dependent kinases (Cdk) promote cell progression, while Cdk inhibitors p16, p21 and p27 counteract the action of cyclin/Cdk complexes. Unphosphorylated retinoblastoma (Rb) protein prevents G1/S transition by hampering the activity of E2F, while hyperphosphorylation inhibits this action of Rb. Other proteins such has the tumor suppressor p53 and the oncogene Myc are also implicated in cell cycle regulation (see text for details).



Transition between the different cell cycle phases is orchestrated by numerous proteins that can be classified into two major functional groups. One class of proteins enables cells to advance in the cell cycle, while the group of proteins has the opposite function and will retain the cells in a specific phase in the cell cycle [Bloom and Cross, 2007]. Proteins that enforce the cells to progress the cell cycle are the cyclin-dependent protein kinases (Cdk). The mammalian genome encodes 9 different Cdk (Cdk1-9), of only which Cdk1, Cdk2, Cdk3, Cdk4, Cdk6, and Cdk7 directly intervene with cell cycle progression [van den Heuvel, 2005]. The activity of these serine/threonine protein kinases is regulated by several mechanisms. First, they associate with a specific interaction partner, referred to as cyclin, to form a cyclin-Cdk complex. The mammalian genome encodes around 16 different cyclins, which will bind to a particular Cdk during certain phases of the cell cycle [Miller and Cross, 2001; Bloom and Cross, 2007]. Since the expression levels of cyclins fluctuate during the cell cycle, the activity of the cyclin-Cdk complexes varies during the different cell cycle stages. The Cdk function is further regulated by phosphorylation and dephosphorylation of specific residues. Full activation of a Cdk requires phosphorylation of a threonine residue adjacent to the kinase active site. This phosphorylation event is mediated by Cdk-activating kinases (CAK). CAK activity remains at a constant and high level throughout the cell cycle and is not regulated by any known cell-cycle control pathway. The major CAK exists as a trimeric complex composed of Cdk7, cyclin H, and Mat1. Interestingly, in addition to its role in the cell cycle, CAK also fulfills a function in transcription [reviewed in Lolli and Johnson, 2005; Fisher, 2005]. Besides activation, phosphorylation can also inhibit the activity of a Cdk. One such inhibitory phosphorylation event occurs at a conserved tyrosine-15 residue in human Cdks. Moreover, phosphorylation of the adjacent threonine-14 further blocks Cdk activity. These residues are located in the ATP-binding site and modifications of these amino acids probably interfere with ATP binding. The phosphorylation state of threonine-14 and tyrosine-15 is controlled by the kinases Wee1 and Myt1 and the phosphatases Cdc25. Thus the opposite activities of Wee1/Myt1 and Cdc25 provide the basis for switching on/off Cdk activity [Kellogg, 2003; Morgan, 2007; Rudolph, 2007].


Proteins that counteract the activity of cyclin-Cdk complexes form one strategy to prevent cell cycle progression. Cdk inhibitors inhibit Cdk’s activity by binding to Cdk and preventing the binding of cyclin. The INK4 (inhibitor of Cdk4) family, which includes the members p16INK4A, p15 INK4B, p18 INK4C, and p19 INK4D, will specifically inhibit Cdk 4 and Cdk 6 and thus prevent G1/S transition. The Cip/Kip family of Cdk inhibitors consists of three members: p21Cip-1, p27Kip-1, and p57Kip-2. p21Cip-1 and p27Kip-1are potent inhibitors of cyclin D, cyclin E, and cyclin A-Cdk complexes, while p57Kip-2 has been less studied [Sherr and Roberts, 1999; Pei and Xiong, 2005; Cánepa et al., 2007].


The tumor suppressors p53 and retinoblastoma (pRb) are two other proteins that are crucial in the regulation of cell cycle progression. It is beyond the scope of this review to discuss their function in the cell cycle. For this, the reader is referred to excellent reviews [Cobrinik, 2005; Giaciniti and Giordano, 2006; Giono and Manfredi, 2006; Vousden, 2006; Blais and Dynlacht, 2007]. For the purpose of this review, it is sufficient to mention that pRb prevents G1/S transition by inhibiting the activity of the transcription factor E2F, which is involved in expression of genes required for the S phase. Hyperphosphorylation of pRb by e.g. cyclin/Cdk complexes releases the inhibitory effect of pRb on E2F and allows the cell to enter the S-phase. The multifunctional p53 protein operates as a negative regulator of cell cycle proliferation and angiogenesis, and controls the apoptosis process. p53 exerts these functions, at least in part, by acting as a transcription factor. The p53-mediated arrest of cell proliferation operates in the G1/S and G2 phases of the cell cycle. In the G1/S phase, p53 stimulates transcription of p21Cip-1, a negative regulator of cyclin E/Cdk2 and cyclin D/Cdk4-6. These cyclin/Cdk complexes promote G1/S transition by phosphorylating pRb during G1 and hence releasing the inhibitory function of pRb on E2F. G2 arrest by p53 is less clear, but it may involve the effectors p21Cip-1and 14-3-3[Vogelstein et al., 2000].


2. The mitogen-activated protein kinase (MAPK) pathway

As the name suggests, mitogens were the first group of signals identified that stimulated these pathways, but also stress and cytokines can elicit activation of the MAPK pathways. MAPK pathways regulate cellular processes such as proliferation, survival/apoptosis, differentiation, development, adherence, motility, metabolism, and gene regulation. The classical mitogen-activated protein kinase (MAPK) signaling pathways consist of cascade of three consecutive phosphorylation events exerted by a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK), and a MAPK. MAPK in turn phosphorylates non-protein kinase substrates or yet other protein kinases. The latter are referred to as MAPK-activated protein kinases (MAPKAPK). Figure 2 illustrates the different MAPK signaling modules identified in mammalian cells [Johnson and Lapadat, 2002; Roux and Blenis, 2004; Imajo et al., 2006; Cuevas et al., 2007; Raman et al., 2007; Weston et al., 2007; Zhang et al., 2007].



Figure 2. The different MAPK cascades in mammalian cells. The typical MAPK pathway consists of a tripartite module in which a MAPKKK phosphorylates a MAPKK, which in turn phosphorylates a MAPK. The natures of the signals that activate the different MAPK cascades are shown at the top of the figure, while some of the substrates are indicated at the bottom of the figure. The poorly identified atypical ERK3, ERK4, ERK7 and ERK8 pathways are also depicted. The figure is adapted from [Imajo et al., 2006].


The MAP kinases ERK1/2, JNK1-3 and p38 MAPK are implicated in cell cycle regulation [reviewed in Zhang and Liu, 2002; Sabapathy and Wagner, 2004; MacCorkle and Tan, 2005; Meloche and Pouysségur, 2007], but also their downstream kinase substrates, the MAPK-activated protein kinases (MAPKAPK) can interfere with cell cycle progression. The mechanisms by which MAPKAPK can modulate the cell cycle will be discussed in detail in the next section.



3. The role of MAPKAPK in cell cycle regulation


3.1. p90 ribosomal S6 kinase or RSK

3.1.1. Properties and function of RSK

RSK was originally detected in Xenopus laevis oocytes as a 90 kDa protein kinase that phosphorylated the 40S ribosomal subunit protein S6. RSK is also known as p90Rsk or MAPKAPK1 because this serine/threonine kinase acts downstream of the MAPK ERK1/2 (Figure 2). RSKs are present in most vertebrate species, as well as in several invertebrates examined [Dai et al., 2008 and references therein]. Two RSK isoforms (RSK1 and RSK2) have been identified in Xenopus, while four mammalian RSK members (RSK1-4) have been described. Though similar in structure to other family members, RSK4 differs in its function from RSK1-3 by the presence of a unique region through which it can inhibit the MAPK signaling pathway. This inhibitory role is dependent on a region that is not conserved in RSK1-3 [Myers et al., 2004]. RSKs are involved in several cellular functions and regulate: i. gene expression by modulating the activity of transcription factors and chromatin remodeling factors; ii. protein syntheses by phosphorylation of polyribosomal proteins; iii. signal transduction pathways such as PKA, NFB, Toll-like receptor signaling through cross-talk; iv. cell survival by targeting proteins involved in apoptosis; v. differentiation; and vi. cell cycle [Frödin and Gammeltoft, 1999; Hauge and Frödin, 2006; Zaru et al., 2008; Gerits et al. 2007a].


3.1.2. The role of RSK in cell cycle regulation

The four isoforms for RSK described in mouse and human (RSK1-4) seem all implicated in cell cycle regulation, but their precise role and the exact mechanisms by which they affect the cell cycle is poorly understood. In the first part of this section, we will review examples of studies that suggest the involvement of RSK isoforms in cell cycle regulation. Then we will elucidate the role and mechanism of RSK1 in cell cycle regulation in oocytes. Finally, we present other mechanisms by which RSK may modulate the cell cycle.


General observations that suggest a role for RSK in cell cycle regulation
RSK1 was reported to be involved in G1/S transition because the specific inhibitor of RSK1, SL0101 (see section 4.), produced a block in the G1 phase of the cell cycle in MCF-7 cell. Similar effects on cell cycle progression were obtained after depletion of RSK1 [Smith et al., 2005]. Although the molecular mechanism remains unclear, these data indicate that in order to pass the G1 restriction point, these cells require RSK1 activity. The RSK2 isoform may also play a role in cell cycle progression because RSK2-/- mouse embryonic fibroblasts accumulate at the G1 phase, while RNA interference showed that knockdown of RSK2 expression arrested the cells in G1 [Smith et al., 2005; Cho et al., 2007]. Depletion of RSK4 strongly reduced the mRNA levels of p21Cip1 and abolished p53-dependent G1 cell arrest induced either by conditional activation by p53 or by DNA damage via ionizing irradiation [Berns et al., 2004]. These observations underscore a role for RSK4 in cell cycle regulation, but the mechanism of action of RSK4 in these processes was not addressed.


The role of the cytostatic factor (CSF) and the anaphase-promoting complex/cyclosome (APC/C) in oocyte maturation
The best understood role of RSK in modulating the cell cycle comes from studies in oocytes of the African clawed frog Xenopus laevis. In most animals, development of immature oocytes into mature oocytes is arrested in the meiotic cell cycle. Unfertilized oocytes then await fertilization before the cell cycle will progress. This arrest occurs at the metaphase of meiosis II in vertebrates and is referred to as cytostatic factor (CSF), where CSF does not describe a single protein, but rather a cell division inhibitory activity in the oocyte. Maturation of oocytes requires the activity of a factor that was originally termed maturation-promoting factor (MPF). MPF is now known to be a universal complex, composed of cyclin B and Cdk1 that drives mitosis and meiosis in all eukaryotic cells. The enzymatic activity of MPF (or cyclin B/Cdk1) changes throughout oocyte maturation, but could be detected in the M-phase from yeast to man. CSF holds the anaphase-promoting complex/cyclosome (APC/C/C) in an active state. APC/C is a mitosis-specific E3 ubiquitin ligase that can induce degradation of cyclin B to promote anaphase entry. Inhibition of APC/C will therefore prevent degradation of cyclin B and this will contribute to activation of cyclinB/Cdk1 (MPF). Thus CSF, which ensures metaphase arrest, can via APC/C affect the activity of MPF, which promotes metaphase→anaphase progression (see Figure 3). RSK, as outlined below, controls the activity of both CSF and MPF.




Figure 3. Pathways involved in maturation of Xenopus laevis oocyte. Immature oocytes are arrested at the border of the first meiotic division (meiosis I). Progesterone induces maturation of the oocytes, allowing them to enter meiosis I and subsequently meiosis II. The oocytes accumulate thereafter in metaphase due to a cell division inhibitory activity referred to as cytostatic factor (CSF). Fertilization of the egg overcomes CSF arrest and allows exit from meiosis II and entry into embryonic division of the fertilized egg. Two pathways contribute to establishment and maintenance of CSF, including cyclinB/Cdk1 (=MPF; maturation-promoting factor) and the MOS-MEK1-ERK-RSK pathway. The anaphase promoting complex/cyclosome (APC/C) governs the levels of cyclin B. In immature oocytes, cyclinB/Cdk1 activity is low because of inhibitory phosphorylation of threonine-14 and tyrosine-15. Progesterone leads to the synthesis of MOS and activation of the MAP kinase cascade MEK1-ERK-RSK. RSK can phosphorylate Emi2, which releases Emi2 from APC/C and activates APC/C. RSK also phosphorylates and activates Bub1, which prevents Cdc20 to activate the APC/C complex. See text for details. The figure is adapted from [Tunquist and Maller, 2003].


A role for RSK in modulating CSF activity derives mainly from injection studies in Xenopus oocytes. Injection of Xenopus blastomeres with constitutive active RSK caused CSF arrest. Later, it was found that an active variant of rat RSK1, as well as a constitutive active variant of mouse RSK2 caused CSF arrest, indicating that mammalian RSK1 and RSK2 possess comparable biological activity in CSF arrest [Silverman et al., 2004 and references therein].


The effect of RSK on the spindle check point component Bub1
One mechanism by which RSK exerts its effect on the cell cycle relies on phosphorylation of Bub1 (budding uninhibited by benzimidazole) protein kinase. This modification leads to inhibition of the anaphase-promoting complex (APC/C). The activity of APC/C is controlled by the co-activators Fizzy/Cdc20 and Cdh1. Fizzy/Cdc20 activates APC/C at the metaphase to anaphase transition, whereas Cdh 1 functions during late mitosis and early G1 phase. Phosphorylation of Bub1 by RSK prevents binding of Fizzy/Cdc20 to APC/C. As a result APC/C is inhibited and this blocks the metaphase/anaphase transition and causes CSF arrest [Schwab et al., 2001; Tunquist et al., 2002; for reviews see Maller et al., 2002; Tunquist and Maller, 2003; Liu et at., 2007]. The spindle assembly/kinetochore attachment checkpoint, required for correct alignment of the chromosomes, forms also restriction point that keeps cells in the metaphase. Once the chromosomes are properly attached, this arrest is relieved and cells enter the anaphase, during which the chromosomes are equally segregated between the two daughter cells. The spindle assembly checkpoint is composed of multiple proteins, including Mad, Bub and Mps. Hence, modulation of the function of spindle checkpoint components (e.g. by RSK-mediated phosphorylation of Bub) can block anaphase progression [reviewed in Tunquist and Maller, 2003 and in Morgan, 2007].


RSK and the APC/C inhibitor early mitotic inhibitor 2 (Emi2)
Another target for RSK is the zinc finger-containing protein Emi2 (early mitotic inhibitor 2; also known as Erp1). During CSF arrest, Emi2 is bound to APC/C and inhibits APC/C function. Upon fertilization, calmodulin-dependent kinase II phosphorylates Emi2, which results in rapid Emi2 degradation. Cdk1 can also phosphorylate Emi2 and this modification disrupts the binding of Emi2 to APC/C. Depletion of Emi2 or dissociation of Emi2 from APC/C alleviates APC/C inhibition, and promotes M phase exit into the first embryonic interphase. RSK can also phosphorylate Emi2, thereby enhancing Emi2’s stability and activity [Nishiyama et al., 2007; Inoue et al., 2007]. In this regard, RSK-mediated phosphorylation of Emi2 at Ser-335 and Thr-336 stimulated the interaction with the protein phosphatase PP2A, resulting in dephosphorylation of Cdk1 phosphorylation sites on Emi2. This increases the stability of Emi2, which maintains CSF arrest through inhibition of APC/C [Wu et al., 2007]. Gross and co-workers also observed a decrease in inhibitory phosphorylation of Cdk1 at Tyr-15 upon microinjection of constitutive RSK1 in Xenopus oocytes, but the exact mechanism was not examined [Gross et al., 2001]. A possible mechanism for RSK-induced dephosphorylation of Cdk1 at Tyr-15 was suggested by the findings of Chen and Gardner and is outlined in Figure 4. They found that RSK was also implicated in endothelin-triggered G2/M progression of vascular smooth muscle cells. Thus, endothelin activates the MEK/ERK pathway which results in the activation of RSK. Active RSK phosphorylates Myt1, which inactivates the enzymatic activity of Myt. Hence, Myt-mediated inhibitory phosphorylation of Cdk1 subsides and Cdk1 becomes activated [Chen and Gardner, 2004]. In another study, an alternative route for RSK2-Emi1-APC/C was identified. The authors showed that RSK2 can phosphorylate the APC/C inhibitor Emi1. This phosphorylation stimulated complex formation between phospho-Emi1 and the APC/C activator Cdc20. Thus in this scenario, Emi1 phosphorylated by RSK2 sequesters Cdc20 from APC and helps to establish CSF arrest during mouse oocyte maturation [Paronetto et al., 2004].




Figure 4. Phosphorylation and dephosphorylation events of Cdk2 and Cdk1 regulate G1/S and G2/M progression, respectively. The Wee1 kinase inactivates Cdk2 through inhibitory phosphorylation. Wee1 itself is inactivated through ERK2-mediated phosphorylation. The phosphatase Cdc25A can remove this inhibitory phosphorylation, converting Cdk2 into an active state. Similarly, Myt1 inactivates Cdk1 through phosphorylation. This inactivation can be counteracted by Cdc25C which dephosphorylates Cdk1 and thereby renders it active. The activities of Myt1 and Cdc2C are controlled by RSK.



RSK and cyclin B
Another mechanism by which RSK may modulate cell cycle progression in oocytes is through stimulation of cyclin B synthesis [Gross et al., 2001]. The molecular mechanism by which RSK stimulates synthesis of cyclin B remains unsolved.



RSK and the Cdk activator Cdc25
One way by which ERK2 may contribute towards G2 arrest is by phosphorylating and activating Wee1, the protein kinase that catalyzes the inhibitory phosphorylation of Cdk1 (Figure 4, left panel). An additional route to prevent G2 exit is through ERK2-induced activation of RSK and subsequent phosphorylation Cdc25C. This will also affect G2/M progression (Figure 4, right panel). It was demonstrated that ERK2 activates RSK, which in turn can phosphorylate Cdc25C at Ser-287. Phosphorylated Cdc25C binds 14-3-3 and keeps Cdc25C in an inactivate state, or/and stimulates nuclear exclusion. As a result, Cdk1 does not become dephosphorylated and the cyclinB-Cdk1 complex is retained inactive. Thus RSK-mediated phosphorylation of Cdc25C at Ser-287 contributes to G2 arrest in Xenopus oocytes [Chun et al., 2005]. The ERK2-RSK pathway may also be used to keep other cell types in the G2 phase. Indeed, treatment of human cervical cancer HeLa cells with epidermal growth factor or with the phorbol ester TPA resulted in delayed M-phase entry and coincided with phosphorylation of and reduction in activity of Cdc25C. Both epidermal growth factor and TPA can activate ERK2, but the involvement of RSK was, however, not tested [Barth et al., 1996].


The role of RSK in oocyte maturation of other species
RSK is not only involved in oocyte maturation of mammals and Xenopus, but also of other species. PhosphoRSK protein levels were differently expressed during developmental stages of Artemia parthenogenetica (brine shrimps), and RSK activation was coupled to termination of G2/M arrest. Moreover, in vivo reduction of RSK activity by either RNA interference, the specific pharmacological inhibitor SL0101, or antibody neutralization with anti-phospho-RSK antibodies resulted in inhibition of mitosis in the cells of Artemia embryos, suggesting a role for RSK in termination of the G2/M arrest and promotion of mitogenesis during the post-embryonic development of Artemia-encysted embryos, although the details remain obscure [Dai et al., 2008]. However, the involvement of RSK in regulation of the cell cycle in oocytes seems to be species specific. While RSK1 and RSK2 contribute to Xenopus laevis oocyte arrest in metaphase of the second meiotic division [Bhatt and Ferrell, 1999; Gross et al., 1999], the RSK isoforms 1, 2, and 3 are dispensable for this arrest in mouse oocytes [Dumont et al., 2005]. Moreover, the phase of cell cycle arrest is also species specific. While the female gametes of most animals are arrested in the meiotic cell cycle awaiting fertilization, the cell cycle in oocytes of starfish (Asterina pectinifera) is arrested in the G1 phase. This arrest requires RSK and inhibition of RSK (by use of an inhibitory antibody) released the arrest and initiated DNA replication without fertilization, while maintenance of RSK activity (by use of a constitutive active variant) prevented DNA replication following fertilization [Mori et al., 2006]. The exact mechanism by which RSK prevents cell cycle progression in unfertilized egg cells of the starfish remains to be solved.


Other mechanisms by which RSK may interfere with cell cycle progression
Another mechanism by which RSK influences the cell cycle is through the Cdk inhibitor p27Kip1. Both RSK1 and RSK2 were demonstrated to directly bind and phosphorylate p27Kip1 at serine-10 and threonine-198 in vivo. The phosphorylation of threonine-198, but not serine-10, promoted the interaction of p27Kip1 with the 14-3-3 isoforms  and , and to a lesser degree to 14-3-3 and 14-3-3. Phosphothreonine 189 could not bind to 14-3-3 and 14-3-3. Binding of the phosphothreonine-198 p27Kip1 to 14-3-3 stimulated cytoplasmic localization of this complex. Since p27Kip1 negatively regulates G1 cell cycle progression by inactivating cyclinE-Cdk2 and cyclinA-Cdk2 complexes, RSK may promote G1/S transition by inducing nuclear exclusion of p27Kip1 [Fujita et al., 2003]. The biological relevance of RSK-mediated phosphorylation of p27Kip1 on serine-10 remains unclear.


The protein kinase LKB1 is a tumor suppressor and mutations in the gene encoding LKB1 has been linked to Peutz-Jeghers syndrome and other diseases, such as diabetes. Peutz-Jeghers syndrome is an autosomal dominantly inherited disorder that predisposes to a wide spectrum of benign and malignant tumors [Katajisto et al., 2007]. LKB1 is a multifunctional protein implicated in preventing proliferation, cell polarity, chromatin remodeling, and the ability of a cell to detect and respond to low cellular energy levels [Alessi et al., 2006]. Overexpression of LKB1 induces a G1 cell cycle block in a number of tumor cells and several MAPKAPK (RSK and MSK1) can phosphorylate LKB1 at Ser-431 in vitro, but studies with pharmacological inhibitors and cells deficient in any of these protein kinases demonstrated that RSK mediates phosphorylation of LKB1 at Ser-431 in cells. This phosphorylation by RSK seems pivotal for LKB1 to induce G1 arrest because cells that were stably transfected with wild-type LKB1 strongly suppressed cell growth, while the LKB1 S431A or S431D mutants could not inhibit cell growth [Sapkota et al., 2001]. The molecular mechanism by which RSK-mediated phosphorylation of LKB1 induces cell cycle arrest remains elusive.


Finally, RSK may indirectly influence the cell cycle through its substrates. Members of the FOS transcription factor family can induce G1/S cell cycle progression by activating cyclin D1 [Brown et al., 1998]. Phosphorylation of the carboxy-terminal region of c-FOS (Ser-362) by RSK leads to stabilization and cellular accumulation of c-FOS [Chen et al., 1993]. Whether this RSK-induced c-FOS stabilization contributes to cell cycle progression remains unknown, but protein kinase D2 could prolong RSK activation, increase c-FOS levels, and stimulate DNA synthesis. These observations support a putative role for RSK in cell cycle progression [Sinnett-Smith et al., 2007]. Additionally, RSK may also regulate the cell cycle through other substrates like CREB, CBP/p300 and NFB, which all have been implicated in cell cycle events, but data directly linking RSK and these proteins to cell cycle regulation lack [Frödin and Gammeltoft, 1999].


3.2. MSK1 and MSK2

3.2.1. Properties and functions of MSK1 and MSK2

The human and mouse genome encodes two mitogen- and stress-activated protein kinases, referred to as MSK1 and MSK2. MSK1 and MSK2 are substrates for both ERK and p38 MAPK and are widely expressed (Figure 2). Studies in cells have assigned a role for MSK1/2 in regulation of translational control (through phosphorylation of the eIF4E-binding protein 4E-BP1) and in transcriptional control (through phosphorylation of transcription factors such as ATF1, CREB, ER81, c-FOS, p65 subunit of NFB, STAT3, and chromatin remodeling factors such as histone H3, HMGN1) [reviewed in Dunn et al., 2005]. The precise biological roles of MSK1 and MSK2 are incompletely understood because single and double knock out mice were viable and fertile, without any obvious phenotype. However, in contrast to control littermates, MSK1-/- mice displayed no enhanced locomotion after repeated cocaine exposure and showed lower preference for cocaine [reviewed in Gerits et al., 2007a]. Moreover, mice lacking MSK1 show impaired Pavlovian fear conditioning and spatial learning [Chwang et al., 2007].


3.2.2. The role of MSK1 and MSK2 in cell cycle regulation

MSK1 phosphorylated the protein kinase LKB1 (see section 3.1.2) at Ser-431 in vitro, but LKB1 did not seem to be a physiological substrate for MSK1. Studies by Sapkota et al. revealed that RSK mediated phosphorylation of LKB1 (see 3.1.). The fact that RSK appears in larger amounts in cells may explain why RSK rather than MSK phosphorylated LKB1 in vivo. On the other hand, stimuli that specifically activate MSK1 did not induce phosphorylation of LKB1 at Ser-431, jeopardizing a role of MSK1 as LKB1 kinase [Sapkota et al., 2001]. MSK1/2 may be indirectly involved in nerve growth factor (NGF) induced G1/S arrest during neuronal differentiation of PC12 cells. NGF treatment resulted in activation of MSK1/2 and this promoted dissociation of the PCAF-PP1/PP2A cytoplasmic complexes, coincident with PCAF phosphorylation and nuclear translocation. PCAF then mediated acetylation of p53 at lysine-320, thereby enhancing the transcriptional activity of p53. As a result, transcription of the p53 target gene encoding cyclin-dependent kinase inhibitor p21Cip1 increased and cells are arrested in G1 phase [Wong et al., 2004].



3.3. MNK1 and MNK2

3.3.1. Properties and function of MNK1 and MNK2

MNK1 and MNK2 (MAPK signal-integrating kinase) were originally identified by screening ERK substrates, but later it was shown that they are activated in vivo by both ERK and p38 MAPK. One single MNK1 protein and two isoforms of MNK2, MNK2a and MNK2b, have been identified in human and mouse. MNK1 and MNK2 can phosphorylate eIF4E (also known as cap-binding protein) at Ser-209, but the biological significance of eIF4E phosphorylation and its effect on the regulation of protein synthesis is controversial [Ueda et al., 2004]. The exact in vivo functions of MNK1 and MNK2 are not known because mice deficient in MNK1, MNK2, or both, appear normal [reviewed in Gerits et al., 2007a]. A recent study reported that transgenic mice expressing a constitutive active MNK1 mutant developed rapid tumors compared to control mice, suggesting that MNK1 can act as an oncogene [Wendel et al., 2007]. MNK1 and MNK2 seem to be involved in anti-apoptotic signaling in response to serum withdrawal as well [Chrestensen et al., 2007].


3.3.2. The role of MNK1 and MNK2 in cell cycle regulation

To our best knowledge, no direct functional link between MNK1 and MNK2 and the cell cycle has been reported so far, although it was demonstrated that overexpression of a dominant negative MNK1 inhibited proliferation of cells [Worch et al., 2004; Wendel et al., 2007]. However, MNK1 and MNK2 may indirectly modulate the cell cycle by regulating the activity of eIF4E, which affects the transport of cyclin D1 mRNA from the nucleus to the cytoplasm or upregulates translation of the mRNA for cyclin-dependent kinase inhibitor p27Kip1 [Topisirovic et al., 2002; Eto, 2006].


3.4. MK2

3.4.1. Properties and function of MK2

Three structurally related enzymes referred to as MK2, MK3/3pK, and MK5/PRAK act downstream of p38 MAPK (Figure 2), but activation by ERK1/2 and JNK has also been observed, at least in vitro. MK2 was the first of these three MAPKAPKs to be isolated and is by far the best studied. This protein kinase is expressed in all invertebrates and vertebrates examined so far, but a structural homolog in yeast is lacking [reviewed in Gaestel, 2006]. Studies with knock-out mice revealed that MK2 is essential for liposaccharide-induced cytokine biosynthesis, which is essential for the inflammatory response [Kotlyarov et al., 1999]. Consistent with this role, MK2 deficient mice show increased susceptibility to infection [Lehner et al., 2002], but the function of MK2 also extends to other cellular processes such as actin remodeling and cell migration by phosphorylation of Hsp25/27, stabilization of mRNA, chromatin remodeling and gene regulation, and regulation of the cell cycle [Heidenreich et al., 1999; Lasa et al., 2000; Janknecht, 2001; Yannoni et al., 2004; Kobayashi et al., 2006; reviewed in Gaestel, 2006].


3.4.2. The role of MK2 in cell cycle regulation

Several observations have pointed to the involvement of MK2 in cell cycle regulation. For example treatment of Swiss 3T3 cells with fibroblast growth factor-2 or hemopoietic cells with granulocyte colony-stimulating factor resulted in proliferation and coincided with strong increase in MK2 activity, suggesting that MK2 can trigger cell cycle progression [Maher, 1999; Rausch and Marshall, 1999]. Both MK2 and MK5 could inhibit Ras-induced proliferation of NIH 3T3 cells. Although the exact mechanism for this anti-mitogenic effect was not known, it was shown that MK2 and MK5 could ablate AP1- and SRE-dependent transcription by inhibiting Ras-induced JNK, but not ERK activation [Chen et al., 2000]. More recent studies have provided insight into the molecular mechanisms by which MK2 may affect the cell cycle.


It is of crucial importance that during cell division the genetic material is correctly passed on to daughter cells. The G2 phase plays an important role as checkpoint for surveillance of the genome and entrance into the M phase can be prevented when DNA damage is observed. Ataxia-Telangiectasia mutated (ATM) and Ataxia-Telangiectasia and Rad-3-related (ATR) are “sensor kinases” that are recruited upon DNA damage (e.g. nucleotide damage, stalled replication forks, and double-strand breaks). ATM and ATR phosphorylate and activate the checkpoint kinases 2 (Chk2) and Chk1, respectively. These kinases are major mediators of cell cycle checkpoints in response to DNA damage. Chk1 is required for the G2/M checkpoint, while Chk2 is operational in the S and G2 checkpoints [Bartek and Lukas, 2003; Bartek and Lukas, 2007]. Chk1 and Chk2 exert their effect through phosphorylation and inactivation of the Cdc25 tyrosine phosphatases. The Cdc25 phosphatases remove inhibitory phosphate groups from Cdks (see above in section 1.) and promote cell cycle progression. Three Cdc25 members have been identified: Cdc25A, Cdc25B, and Cdc25C. The latter two are primarily involved in regulating mitotic entry through their activation of cyclinB/Cdk1, while Cdc25A controls both progression through S phase, and entry into and maintenance of mitosis [Abraham, 2005; Morgan, 2007]. Recently, p38 MAPK and MK2 have been reported to mediate phosphorylation of the Cdc25 family members. While Bulavin and colleagues reported that p38 MAPK phosphorylates Cdc25B at Ser323 and Ser375, and Cdc25C at Ser216 in response to ultraviolet radiation , Manke and colleagues showed that MK2, which associates to and is activated by the p38 MAP kinase, is directly responsible for phosphorylation of Cdc25B at these sites in vitro and in response to UV-induced DNA damage in vivo. Cell treated with siRNA targeting MK2 eliminated G1 arrest and G2/M and S phase checkpoints following UV-induced DNA damage . However, later on, Lemaire et al. re-examined the phosphorylation of Cdc25B by the MK2 and p38 kinases. They determined that MK2 phosphorylated Cdc25B on multiple sites including Ser169, Ser323, Ser353 and Ser375, while p38 phosphorylated Cdc25B on Ser249 . Phosphorylation of Cdc25B/C inhibits these phosphatases, and hence prevents removal of the inhibitory phosphatases on Cdks. As a result, cells are maintained in the G2/M checkpoint [Abraham, 2005; Morgan, 2007]. The finding that G1 and S phase checkpoints were eliminated in the MK2 depleted cells indicates that MK2 may also be involved in Cdc25A phosphorylation . Indeed, MK2 depletion in p53-deficient cells, but not in p53 wild-type cells, caused abrogation of the Cdc25A-mediated S phase checkpoint after cisplatin exposure and loss of the Cdc25B-mediated G2/M checkpoint following doxorubicin treatment [. On the other hand, Xiao and co-workers found that siRNA-mediated depletion of Chk1, but not Chk2 or MK2, was sufficient to abrogated S phase and G2 phase arrest after genotoxic stress-induced DNA damage. However, simultaneous knockdown of Chk1 and MK2 partially reversed the checkpoint abrogation observed with siRNA against Chk1 alone, which indicates that the antagonist effect of MK2 resides on Cdc25A [Xiao et al., 2006]. While depletion of Chk1 increased Cdc25A levels, which is consistent with the role of Chk1 in targeting Cdc25A for degradation [Xiao et al., 2003], loss of MK2 expression destabilized Cdc25A protein. Hence, MK2 may prevent Chk1-induced degradation of Cdc25A, which is required for the checkpoint abrogation and cell cycle progression [Xiao et al., 2006].



Another mode by which MK2 may interfere with the cell cycle is through modulating the activity of p53. MK2 can induce degradation of p53 by mediating phosphorylation of MDM2 (or its human homolog HDM2). This post-translational modification enhances MDM2/HDM2 activity and promotes the degradation of p53. Accordingly, increased p53 protein levels were monitored in MK2-/- MEF cells compared to wild-type cells [Weber et al., 2005]. MK2 was also demonstrated to phosphorylate p53 on Ser20 in vitro and phosphorylation of this site disrupts the in vivo interaction with MDM2 and enhances p53’s stability [She et al., 2002]. The exact biological consequences of MK2-mediated stabilization of p53 on cell cycle control remains elusive despite a functional link between p53 and MK2.


Huard et al. proposed that human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) could also induce cell cycle G2 arrest through modulation of the MK2 kinase. Vpr activates MK2 by direct protein-protein interaction. The activated MK2 phosphorylates Cdc25, which binds to 14-3-3 and translocates from the nucleus to the cytoplasm through an active nuclear-cytoplasmic shuttling, which involves Crm-1. Consequently, nuclear exclusion of Cdc25 prevents dephosphorylation of Cdk1, and results in hyper-phosphorylation of Cdk1 leading to the cell cycle G2 arrest [Huard et al., 2007].


3.5. MK3

3.5.1. Properties and function of MK3

MK3/3pK was detected by two independent research groups by two different approaches. The team of Rapp identified the gene encoding MK3 when they analyzed chromosome 3p21.3 in small lung cancer tumor suppressor gene region, while McLaughlin and colleagues identified MK3 when searching for interaction partners for p38 MAPK [Ludwig et al., 1996; McLaughlin et al., 1996; Sithanandam et al., 1996]. MK3 expression is restricted to birds and mammals and its activation exclusively depends on p38/ MAPK [reviewed in Gaestel, 2006]. Furthermore, MK3 regulates chromatin remodeling/transcriptional activation via polycomb, a multi-protein complex that contributes to stable silencing of specific genes and repression of the transcription factor E47 [Neufeld et al., 2000; Voncken et al., 2005].


3.5.2. The role of MK3 in cell cycle regulation

So far, no direct role for MK3 in the cell cycle has been identified. However, overexpression of MK3 resulted in de-repression of the gene encoding the p53-stabilizing protein p14/p19ARF and slowed down cell cycling [Voncken et al., 2005]. MK3-induced cell cycle arrest corresponds well with the known biological feature of ARF to induce both G1 and G2 arrest (and hence senescence; see 3.6.2.) due to its stabilizing effects on the p53 transcription factor [Gallagher et al., 2006; Sherr, 2006].


3.6. MK5

3.6.1. Properties and function of MK5

In 1998 a novel MAPKAPK was identified by two independent laboratories and named MAPKAPK-5 (MK5) or PRAK (p38-regulated and –activated kinase), respectively. PRAK is the human homolog of MK5 [New et al., 1998; Ni et al., 1998]. MK5 seems to be ubiquitously expressed in all vertebrates examined so far, but is absent in Caenorhabditis elegans and Drosophila [reviewed in Gaestel, 2006]. The biological functions of MK5 are poorly understood. To determine the in vivo role of MK5, knock out mice or mice that express a constitutive active MK5 mutant were generated. Depending on the genetic background of the mice, MK5-/- animals appear normal with no obvious phenotype (129xC57BL/6 background) or have increased embryonic lethality (C57BL/6 background) [reviewed in Gerits et al., 2007a]. MK5 deficient mice do not develop spontaneous tumors within 2 years after birth, but display increased sensitivity to chemical-induced skin cancer. Moreover the authors showed that MK5 mediated senescence upon activation by p38 MAPK in response to oncogenic p21RAS, and that MK5 deficiency rendered primary cells more susceptible to oncogenic transformation, suggesting a tumor suppressing role for MK5 [Sun et al., 2007]. Mice expressing a constitutive active MK5 demonstrated anxiety-related traits and locomotor differences compared to their control littermates, which may implicate a role for MK5 in neurological processes [Gerits et al., 2007b]. Moreover, we recently characterized an in vivo interaction between the PKA and MK5 and demonstrated that MK5 is involved in PKA-induced microfilament rearrangement [Gerits et al., 2007c].


3.6.2. The role of MK5 in cell cycle regulation

Senescence, a permanent state of cell-cycle arrest, develops naturally in most cells after repeated cell division, but can be induced prematurely by multiple DNA damage, telomere dysfunction, derepession of the INK4a/ARF locus and other stimuli. Senescence suppresses the development of cancer cells by arresting the proliferation of damaged cells that are at risk for malignant transformation [Campisi and d’Adda di Fagana, 2007; Collado et al., 2007; Yaswen and Campisi, 2007]. A previous study had demonstrated that wild-type, but not a kinase dead mutant of MK5 could prevent p21RAS-induced proliferation in NIH3T3 cells [Chen et al., 2000]. In a later studie, Sun and colleagues expanded this finding by showing that MK5 mediated activated (oncogenic) p21RAS-induced senescence and that MK5 was required for p21RAS-induced silencing of cyclin A. Moreover, MK5 phosphorylated p53 at Ser-37 in the transactivation domain and stimulated the transcriptional activity of p53 [Sun et al., 2007]. Thus both MK3 and MK5 may be involved in senescence, MK3 by ARF-mediated stabilization of p53 and MK5 by increasing the activity of p53 through direct phosphorylation at Ser-37.

.

One genuine substrate for MK5 is the atypical MAPK ERK3 [Schumacher et al., 2004; Seternes et al., 2004]. The interaction between ERK3 and MK5 stabilizes ERK3. It was recently shown that ERK3 directly binds cyclin D3, as well as Cdc14A (an antagonist of cyclin-dependent kinase 1), and that Cdc14A stabilizes complex formation between ERK3 and cyclin D3 [Sun et al., 2006; Hansen et al., 2007]. These findings suggest a putative role for ERK3 in the cell cycle. Because MK5 binds to and phosphorylates ERK3 and stabilizes ERK3 [reviewed in Gaestel, 2006], MK5 may through ERK3 affect the cell cycle. Moreover, overexpression of ERK3 inhibits S phase entry in mouse NIH3T3 fibroblasts. Enrichment of ERK3 in the nucleus or in the cytoplasm markedly attenuated ERK3’s ability to block S phase entry, indicating that nucleocytoplasmic shuttling of ERK3 is important [Julien et al., 2003]. We and others have previously shown that co-expression of ERK3 and MK5 results in nuclear exclusion of ERK3 [Schumacher et al., 2004; Seternes et al., 2004]. Thus MK5 could through retaining ERK3 in the cytoplasm prevent ERK3 to inhibit G1/S phase transition.


4. MAPKAPK inhibitors and therapeutic applications

The implication of MAPKAPK in cell cycle regulation makes these protein kinases attractive therapeutic targets in conditions with perturbed cell cycling. In the last years, tremendous efforts have been made to design specific MAPKAPK inhibitors. Some examples will be discussed here.


During the screen of botanical extracts obtained from Forsteronia refracta, a member of the Apocynacae (dogbane) family, a RSK-specific inhibitor was identified. This kaempferol glycoside compound was originally named SL0101 (3-O-(3'',4''-di-O-acetyl-alpha-l-rhamnopyranoside). SL0101 interacts with the amino-terminal kinase domain of RSK where it competes with ATP for the nucleotide binding site. Although SL0101 inhibited RSK, it did not alter proliferation of the normal human breast cell line MCF-10A, but it did inhibit proliferation of the human breast cancer cell line MCF-7. Proliferation of human prostate cancer cell lines LNCaP and PC-3 was also abrogated by this inhibitor. Interestingly, these cancer cells displayed higher expression levels of RSK1 and RSK2 compared to normal cells. The antiproliferative properties of SL0101 and the findings that SL0101 is membrane permeable and not toxic for cells makes this compound an attractive chemotherapeutic agent in cancer treatment [Clark et al., 2005; Smith et al., 2005].


MNK regulates proinflammatory cytokine production and the non-toxic MNK inhibitor CGP57380 as been proposed for therapeutic use in breast cancer patients, Crohn’s disease patients, and individuals suffering from prophylaxis and metabolic disorders [Rowlett et al., 2008; Chrestensen et al., 2006; www.wipo.int/pctdb/en/wo.jsp?WO=2003%2F037362&IA=WO2003%2F037362&DISPLAY=DESC].


Sha and co-workers identified a peptide, CBP501, which inhibits MK2 and therefore MK2-mediated phosphorylation of Cdc25C. Phosphorylation of Cdc25C prevents it from activating cyclin B/Cdk1, the master control switch of the transition from G2 to M phase. Thus CBP501 may be used as a G2-abrogating drug, which is a promising strategy to kill cancer cells as most of them depend on G2 checkpoint to survive with DNA damage [Sha et al., 2007].

5. Conclusion

Loss of normal cell cycle regulation and uncontrolled cell proliferation, a hallmark for tumor cells, can result from perturbed action of protein kinases [Greenman et al., 2007]. The last decennium has therefore seen an explosion in the development of specific protein kinase inhibitors and their use in clinical trials [Mikalsen et al., 2006]. MAPKAPK seem to be implicated in cell cycle progression, but a putative role for all known MAPKAPK in cell cycle control has not been addressed. A challenge for future research is to scrutinize the mechanisms by which MAPKAPK can affect the cell cycle. Generating mouse models or cell lines deficient in MAPKAPK or the use of RNA interference to knock down the expression of a particular MAPKAPK may increase our knowledge of the functions of that MAPKAPK. A better understanding of the fine molecular mechanisms by which a certain MAPKAPK affects the cell cycle may allow the development of highly efficient and specific MAPKAPK inhibitors.


6. Acknowledgement

Research in our laboratory is financed by the Norwegian Cancer Society (Kreftforeningen; projects A01307).

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