Email updates

Keep up to date with the latest news and content from Journal of Molecular Signaling and BioMed Central.

Open Access Review

Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5

Sergiy Kostenko, Gianina Dumitriu and Ugo Moens*

Author Affiliations

Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, NO-9037, Norway

For all author emails, please log on.

Journal of Molecular Signaling 2012, 7:9  doi:10.1186/1750-2187-7-9


The electronic version of this article is the complete one and can be found online at: http://www.jmolecularsignaling.com/content/7/1/9


Received:20 April 2012
Accepted:20 June 2012
Published:16 July 2012

© 2012 Kostenko et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Perturbed action of signal transduction pathways, including the mitogen-activated protein (MAP) kinase pathways, is one of the hallmarks of many cancers. While the implication of the typical MAP kinase pathways ERK1/2-MEK1/2, p38MAPK and JNK is well established, recent findings illustrate that the atypical MAP kinase ERK3/4-MK5 may also be involved in tumorigenic processes. Remarkably, the ERK3/4-MK5 pathway seems to possess anti-oncogenic as well as pro-oncogenic properties in cell culture and aninal models. This review summarizes the mutations in the genes encoding ERK3, ERK4 and MK5 that have been detected in different cancers, reports aberrant expression levels of these proteins in human tumours, and discusses the mechanisms by which this pathway can induce senescence, stimulate angiogenesis and invasiveness.

Keywords:
PRAK; RAS; c-MYC; IGB2PB; Angiogenesis; Senescence; HSP27; FOXO3a

Introduction

Mitogen-activated protein kinase pathways

The mitogen-activated protein kinase (MAPK) pathways play crucial roles in cell proliferation, differentiation, gene expression, apoptosis, metabolism and motility [1-5]. A typical MAPK pathway consists of a cascade of three consecutive phosphorylation events exerted by serine/threonine kinases known as MAPK kinase kinase (MAPKKK or MAP3K), a MAPK kinase (MAPKK or MAP2K), and a MAPK (Figure 1, [1-5]).

thumbnailFigure 1. Schematic presentation of the different mammalian MAP kinase pathways. The conventional MAP kinase pathways, represented by the MEK/ERK, JNK, p38MAPK, and MEK5/ERK5 pathways, consist of a module of three kinases that subsequently phosphorylate and active each other. The MAPK kinase kinase (MAP3K) phosphorylates MAPK kinase (MAP2K), which in turn phosphorylates MAPK. Downstream of MAPK are substrates including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPK). The atypical pathways include ERK3, ERK4, ERK7, ERK8, and NLK. MAPKs can converge to different MAPKAPK as shown in this figure.

Substrates of MAPKs include protein kinases designated as MAPK-activated protein kinases (MAPKAPK). The human MAPKAPK family comprises the ribosomal-S6-kinases (RSK1-4), the MAPK-interacting kinases (MNK1 and 2), the mitogen-and stress-activated kinases (MSK1 and 2), and MAPKAPKs MAPKAPK-2 (MK2), MAPKAPK-3 (MK3), and MAPKAPK-5 (MK5) [6-10]. RSKs are downstream targets of the

    e
xtracellular signal-
    r
egulated
    k
inases ERK1, ERK2 and ERK5, and regulate cell growth, cell proliferation, cell survival, transcription and translation, and cell motility [5,11-13]. MNK1 and MNK2, which are activated in vivo by ERK1/2 and p38MAPK, participate in transcriptional and translational regulation, inflammatory responses, proliferation and survival [8,14]. MSK-1 and MSK-2 operate downstream of ERK1/2 and p38MAPK, and play versatile roles in transcription, translation, inflammatory responses, and neuronal processes [7,10]. Of MK2, MK3 and MK5, MK2 and MK3 are most closely structurally and functionally related. They share 75% overall sequence identity and are directly activated by p38MAPK[6,15]. MK2 participates in cytokines production, endocytosis, cytoskeleton architecture, cell migration, cell cycle control, cell survival, and transcriptional regulation and may play a causal role in infections and inflammatory diseases such as rheumatoid arthritis, atherosclerosis, and asthma [6,14-16]. The precise role of MK3 is not fully understood because MK3 deficient mice are viable and display no obvious phenotype. However, studies in a MK2-deficient background indicated that MK3 can compensate for the loss of MK2, while MK3 seems to inhibit interferon-γ expression by impairing interferon regulatory factor 3 protein expression and activation and inhibiting nuclear translocation of the p65 subunit of NFκB [17,18].

MAPK ERK3 and ERK4

The human ERK3 (~100 kD) and ERK4 (~70 kD) proteins have a similar structural organization and are 73% identical in their kinase domain. Both are atypical MAPK because their activation loop lacks a phosphoacceptor Tyr residue (conserved TXY motif), but contains a Ser-Glu-Gly (SEG) motif [5,19]. ERK4 is a relative stable protein, while ERK3 is rapidly degraded via the ubiquitin-proteasome pathway [20-23]. When overexpressed in cells, both ERK3 and ERK4 redirect MK5 exclusively to the cytoplasm [20,21,24]. ERK3 and ERK4 can be activated by the group I p21-activated protein kinases PAK1, PAK 2, and PAK3 [25,26].

ERK3 deficient mice on a C57BL/6 background are non-viable [27]. Approximately 40% of the born offspring die within 15 min of delivery because of acute respiratory failure, while the survivors display severe phenotypic changes such as uncoordinated movements, lack of reflex on pinching, infirm vocalization, and diminished suckling reflex. The surviving animals die within 24 h after birth. ERK3−/− mice have foetal growth restrictions and reduced body and organ weight, but no gross morphological changes. Moreover, they are characterized by pulmonary hypoplasia and incomplete differentiation of type II pneumocytes, confirming a role of ERK3 in differentiation and proliferation. ERK3−/− mice display also defects in production and/or secretion of insulin-like growth factor II [27].

Disruption of the mapk4 gene encoding ERK4 has no obvious effects on viability, fertility, morphology and physiology of the mice on a mixed C57BL/6 J × 129/Sv genetic background [28]. Moreover, knockout of the mapk4 gene in ERK3 deficient mice does not exacerbate their phenotype. However, ERK4-deficient animals on a C57BL/6 J genetic background possess increased depression-like behaviour [28]. The cellular and physiological roles of ERK4 remain obscure.

Mitogen-activated protein kinase-activated protein kinase-5 (MK5)

MK5 is a 54 kD ser/thr kinase that can be activated in vitro by ERK2, JNK and p38MAPK through phosphorylation of Thr-182 [29,30]. MK5 is ubiquitously expressed, but is most abundant in brain, heart and platelets [29-31]. The organization of the gene and primary sequence of the protein are well conserved in vertebrates, but a gene encoding MK5 seems absent in invertebrates [32]. MK5 has a functional nuclear localization signal and nuclear export signal that allows the protein to shuttle between the nucleus and the cytoplasm. In resting cells, MK5 is predominantly found in the nucleus [24,33]. The N-terminal region of MK5 contains the catalytic domain, while the C-terminal region is required for ERK3 and ERK4 binding. MK5 also contains a p38MAPK docking motif, which overlaps with the nuclear localization signal [32].

Although the amino acid sequence and the structural organization of MK5 show most similarity to MK2 and MK3 (approximately 33% homology,), several unique properties clearly distinguish MK5 from MK2/MK3. MK5 has a unique C-terminal sequence which is lacking in MK2 and MK3 [5,6,30,32]. In contrast to MK2 and MK3, MK5 belongs to the atypical MAPK pathways (Figure 1, [5]). ERK3 and ERK4 are upstream activators of MK5 that can induce phosphorylation of MK5 at Thr-182 [20,21,34-36]. PAK-induced activation of ERK3/4 results in increased phosphorylation of MK5 at Thr-182 and stimulated the enzymatic activity of MK5 [25,26]. There is controversy to whether p38MAPK can phosphorylate MK5 on Thr-182 in vivo, but recent results show that the p38β isoform can activate MK5 in vivo[37,38]. Another activator of MK5 is cAMP-dependent protein kinase (PKA) which phosphorylates MK5 at Ser-115 [24,39].

The biological role of MK5 remains incompletely understood. MK5 knockout mice generated on a mixed 129 × C57/B6 genetic background are viable, fertile and display no obvious phenotype, while mk5−/− mice on a C57BL/6 genetic background show embryonic lethality with incomplete penetrance around E11 [35,40]. Transgenic mice overexpressing a constitutive active mutant of MK5 display sex-specific changes in anxiety behaviour and locomotor activity, but the underlying molecular mechanisms have not been identified [41].

Association of ERK3/4-MK5 pathway with cancer

Effect of ERK3, ERK4 and MK5 on cell proliferation

Several observations disclose an involvement of the ERK3/4-MK5 pathway in cell cycle regulation (Figures 2 and 3). Elevated ERK3 levels result in G1 cell cycle arrest and inhibition of cell proliferation [22,42,43]. So far, it is not known whether ERK4 is implicated in cell cycle regulation because no difference in the proliferation rate between wild-type and ERK4−/− fibroblasts was observed [28]. Overexpression of wild-type, but not kinase dead MK5 inhibited oncogenic H-Ras induced cell proliferation of NIH3T3 cells [44]. Ectopic expression of MK5 alone also reduced proliferation of NIH3T3 cells [45]. Oncogenic H-Ras-induced senescence is compromised in MK5 deficient primary murine fibroblasts and embryonic fibroblasts. Wild-type MK5, but not a kinase-dead mutant restored the senescence response to oncogenic Ras, indicating that the enzymatic activity of MK5 is required [46]. Knockout of the mk5 gene in mouse embryonal fibroblasts leads to cell cycle arrest and proliferation inhibition [47].

thumbnailFigure 2. Molecular mechanisms of the pro- and anti-oncogenic properties of ERK3, ERK4, and MK5. (1,2) Oncogenic Ras mutants can increase the transcript levels of ERK4, but also results in constitutive activation of Raf. (3) Activated Raf or oncogenic BRAFV600E also stimulates transcription of the erk3 gene. (4) The RNA binding protein IGB2BP can inhibit translation of ERK4 mRNA. (5) ERK3 and ERK4 proteins can activate MK5. (6) Active MK5 can phosphorylate Hsp27, which will affect actin remodelling and cell migration. (7) MK5 can also phosphorylate transcription factor FOXO3a, which in turn will trigger transcription of microRNA mir34b/c. mir34b/c inhibits the cell cycle and prevents translation of c-myc mRNA and hence the production of c-MYC, a protein that is important for cell cycle regulation. C-MYC binds to the promoter of the mk5 gene and enhances transcription of this gene. FOXO3a also reduces expression of VEGF and may thus hamper angiogenesis. (8) MK5-mediated phosphorylation of p53 at Ser-37 stimulates the transcriptional activity of p53, resulting in enhanced expression of p21Cip1. p21Cip1 inhibits cell cycle progression. (9) ERK3 can sequester cyclin D3. By usurping cyclin D3, it may cause cell cycle arrest.

thumbnailFigure 3. MK5 is implicated in VEGF-mediated angiogenesis. VEGF produced by tumour cells will bind to the VEGF receptor VEGFR2 on endothelial cells. This will trigger a cascade involving the MAP kinases p38 and MK5. MK5 can in turn activate FAK, and this will result in changes in the cytoskeletal architecture and migration of endothelial cells towards the tumour. A blood vessel with endothelial cells aligning the vessel is shown. The pathway induced by VEGF and which involves MK5 is depicted in detail.

Somatic mutations in the erk3, erk4 and mk5 genes in human tumour tissues

A limited number of samples of a restricted selection of cancers have been examined for mutations in the erk3, erk4 and the mk5 gene. Silent mutations or single amino acid substitutions have been detected in lung, ovary and skin cancer tissue for ERK3, in lung and skin cancer tissue for ERK4, and in lung, melanoma and ovary cancer samples for MK5 (Tables 123; [48-54]). The effect of these mutations on the biological properties of ERK3, ERK4 and MK5 needs to be investigated, and it is has to be determined whether these are driver or passenger mutations. Interestingly, the L290V substitution in ERK3 was observed in both lung and skin cancer samples [48,51]. The E331D and D336N substitutions in ERK4 are located in the MK5 interaction motif [55]. In an overlay assay using ERK4 peptides with wild-type sequence or single amino-acid substitutions bound to cellulose membrane, the authors showed that D336N, but not E331D reduced in vitro binding of recombinant MK5. This observation may indicate that the in vivo interaction between ERK4 D336N and MK5 is weakened and affects the ERK4-MK5 signalling. ERK4 mutations A52V and P246T reside in the kinase domain, but it is not known if they affect the catalytic activity of ERK4.

Table 1. Somatic mutations in mapk6/erk3 in cancer tissues

Table 2. Somatic mutations in mapk4/erk4 in cancer tissues

Table 3. Somatic mutations in mapkapk-5 in cancer tissues

Altered expression of ERK3, ERK4 or MK5 in cancer tissue

The expression of proliferating cell nuclear antigen (PCNA), a key regulator in cell cycle control, DNA replication and repair, is strongly upregulated in many chronic myelogenous leukaemia (CML) patients. siRNA-mediated depletion of PCNA expression in several CML cell lines resulted in down-regulation of PAK2 and ERK3 transcript levels [56]. This may suggest that in CML patients with enhanced PCNA expression, the levels of PAK2 and ERK3 are also elevated and these perturbed expression levels may be implicated in the development of CML. Rai and colleagues examined the levels of ERK3 transcripts in oral tissue and peripheral blood cells from patients with chewing-tobacco-induced oral squamous cell carcinoma and healthy controls [57]. They found that 37/41 (90%) of the patients examined displayed a 5- to 8-fold increase in ERK3 transcripts in oral cancer tissue compared to healthy tissue. Peripheral blood cells of 8/13 (61.5%) oral squamous cell carcinoma patients also showed increased ERK3 mRNA levels, compared to absence or low levels in 71% (23/31) in peripheral blood cells of healthy individuals. Sequencing of the erk3 gene of oral squamous cell carcinoma tissue revealed that the coding sequence was identical with the sequence of the erk3 gene determined from foetal skeletal muscle. However, the oral cancer erk3 gene sequence had 4 nucleotide alterations in the non-coding region. Although it was not tested whether all oral cancer patients with increased ERK3 transcript levels carried the same mutations in their erk3 gene, the authors speculated that these mutations may affect the stability or translation efficiency of ERK3 mRNA, resulting in overexpression of ERK3. The presence of relatively high ERK3 transcripts in peripheral blood of healthy individuals may indicate that these individuals are at higher risk of developing oral cancer [57].

Oncogenic mutations in the b-raf gene, especially activating V600E mutation, is very common in several forms of cancer [58,59]. Inducible expression of oncogenic BRafV600E in NIH3T3 cells resulted in ~10-fold increased transcript levels of ERK3 and augmented protein levels compared to control cells [60]. Studies with proteasomal inhibitors demonstrated that BRafV600E exclusively regulates ERK3 expression at the transcriptional level without affecting proteasome-mediated turnover of ERK3 protein. The mechanism by which BRafV600E enhances ERK3 transcription is not known, but knockdown of BRafV600E in the melanoma cell line A375 or inhibition of MEK1/2, but not p38MAPK by respectively U0126 and SB203580, abrogated ERK3 expression. Whether ERK3 contributes to tumorigenesis in melanoma expressing BRafV600E remains elusive because depletion of ERK3 in A375 cells did not change tumour cell proliferation, apoptosis or angiogenesis in mice injected with A375 cells stably transfected with ERK3 shRNA [60]. PAK3 is an upstream activator of ERK3 [25,26]. Pak3 mRNA levels, however, were downregulated upon induction of BRafV600E expression [60]. These results indicate that BRafV600E-induced transcriptional upregulation of the erk3 gene is independent of PAK3. Wang and co-workers found that 10/21 colorectal cancer tissues had higher ERK3 expression levels that adjacent normal mucosa [61]. Elevated ERK3 protein levels are also associated with gastric cancer. The protein levels of ERK3 were on average 3.85-fold higher in 27/42 gastric cancer tissues compared with paired adjacent normal mucosa samples [62]. ERK3 levels were higher in stage II and stage III tumours than in stage I and stage IV tumours. Metastatic lymph nodes (n = 14) had on average 6.9-fold higher ERK3 protein levels than adjacent mucosa specimens [61]. Determination of relative ERK3 transcript levels by quantitative real-time PCR in 48 mouse salivary gland tissues (7 normal, 13 dysplasias, and 28 adenocarcinomas) showed increased levels in dysplasia and adenocarcinomas compared to normal tissue [63]. Increased ERK3 transcripts or protein levels have also been observed in breast cancer, melanoma and non-small cancer lung cells [64-66]. It remains to be established whether increased ERK3 levels contribute to oncogenesis.

Less is known about ERK4 and MK5 protein levels in cancers. Lung adenomas in oncogenic K-Ras transgenic mice contain increased ERK4 levels compared with lungs of non-transgenic mice, but the biological relevance is not known [67]. To our best knowledge, no aberrant MK5 protein levels in tumours have been reported so far.

Molecular mechanisms of the oncogenic potentials of the ERK3/4-MK5 signalling pathway

The fine molecular mechanisms by which ERK3 prevents cell cycle progression are incompletely understood, but ERK3 binds cyclin D3, as well as Cdc14A (an antagonist of cyclin-dependent kinase 1), while Cdc14A stabilizes complex formation between ERK3 and cyclin D3 [68]. ERK3 may sequester cyclin D3, thereby inhibiting cell cycle progression [68].

Long et al. [66] elegantly demonstrated that ERK3 promotes lung cancer cell invasion in vitro and in vivo through upregulating the expression of matrix metalloproteinase MMP2 and MMP10. ERK3 enhances transcription of the MMP2 and MMP10 genes by phosphorylating the steroid co-activator SRC-3 at Ser-857, which is essential for the interaction of SRC-3 with transcription factor PEA3. MMP2 and MMP10 are SRC-3/PEA3 target genes [66].

A causal role for ERK4-MK5 in metastasis was recently proposed [69]. Insulin-like growth factor 2 mRNA-binding protein (IGF2BP, also known as IMP, VICKz or ZBP1) belongs to a family of highly conserved proteins that regulate stability, location, and translation of a subset of mRNAs and as such, participate in cell polarity and migration [70,71]. IMPs are overexpressed in various human cancers where they are implicated in the formation of lamellipodia and invadopodia, and thus may contribute to metastasis [69,72-74]. A recent study by Stöhr and co-workers unveiled a role of the ERK4-MK5 pathway in IGF2BP- induced tumour cell migration [69]. Microarray analysis of total RNA isolated from stressed osteosarcoma U2OS cells upon IGF2BP1knockdown identified 74 annotated transcripts decreased ≥8-fold compared to control cells. One of the transcripts encodes ERK4. The authors showed that IGF2BP1prevents translation of ERK4 mRNA, which antagonizes MK5 activation and HSP27 phosphorylation. Knockdown of IGF2BP1 promoted HSP27 phosphorylation at Ser-78 and Ser-82, while overexpressing IGF2BP1 decreased ERK4 and phosphoHSP27 levels. While phosphoThr-182 of MK5, which is required for MK5 activation, was not examined, the authors showed that siRNA-mediated depletion of MK5, as well as inhibition of MK2/MK3/MK5 by Hsp25 kinase inhibitor reduced HSP27 phosphorylation. Phosphorylation of HSP27 controls actin dynamics [reviewed in [75], and indeed IGF2BP1 knockdown-triggered changes in the actin cytoskeleton were abolished by both depletion and inhibition of MK5 [69]. The authors used time-lapse microscopy to demonstrate that IGF2BP1 promoted the velocity of cell migration by inhibiting MK5-mediated phosphorylation of HSP27. MK5-induced HSP27 phosphorylation leads to a significant decrease in cell migration velocity. Thus, overexpression of IGF2BP1 protein in cancer cells results in inhibition of ERK4 mRNA translation and activation of MK5, and subsequent reduction in HSP27 phosphorylation. This promotes the velocity of tumour cell migration. Interestingly, tumour cells often display elevated HSP27 levels [reviewed in [75]. Thus increased IGF2BP1 and HSP27 protein levels both promote cell migration/invasiveness.

MK5 may exert anti- and pro-oncogenic effects as demonstrated by two studies from the group of Sun. In a first study, this group described that MK5 knockout mice were more susceptible to 7,12-dimethylbenzathracene (DMBA)-induced skin cancer [46]. The authors postulated that MK5 suppresses the initiation stage of skin carcinogenesis by mediating oncogene-induced senescence. The exact mechanism by which MK5 can act as a negative regulator in oncogenic RAS proliferative signalling is incompletely understood, but MK5’s ability to suppress cell proliferation relies on intact kinase activity and nuclear localization, because neither kinase dead mutants nor mutants that reside in the cytoplasm can prevent oncogenic RAS-induced cell proliferation [45,46]. The authors provided evidence that MK5 transactivates p53 through phosphorylation of Ser-37, resulting in increased expression of p21Cip-1 and subsequently cell cycle arrest [46]. Additionally, MK5 inhibited RAS-induced JNK activity by 85% [44]. The JNK pathway is implicated in proliferation and can act as a negative regulator of the p53 tumour suppressor [76,77]. These observations suggest a dual pathway by which MK5 prevents oncogenic RAS-induced cell proliferation. The fine molecular mechanism by which MK5 interferes with the JNK pathway is not known, nor has a functional link in cancer been established.

In a later study, the same group showed that once the tumour is established, tumour growth was drastically impaired in MK5−/− mice, while sustained growth and malignant progression of tumours was observed in MK5+/+ and MK5+/− mice [78]. MK5 supports tumour growth and progression by stimulating angiogenesis. MK5 mediates endothelial cell migration in response to vascular endothelial growth factor (VEGF) and maybe additional factors secreted by the skin tumour epithelium (Figure 3). VEGF binds predominantly VEGF receptor 2 (VEGFR2) and this triggers MK5 Thr-182 phosphorylation through a cascade involving the p38MAPK isoforms α and β, but not ERK3 and ERK4 [78]. Activation of the p38MAPK pathway by VEGF has been shown to induce phosphorylation of HSP27 and to provoke actin reorganization and migration of endothelial cells [79]. Although HSP27 is a genuine substrate of MK5 [80] and MK5 can be activated by p38MAPK, VEGF-induced HSP27 phosphorylation was not affected in MK5 depleted human vascular umbilical veil endothelial cells. Focal adhesion kinase (FAK) is another major regulator of cytoskeletal organization and cell migration [81]. Yoshizuka and colleagues demonstrated that VEGFR2-induced MK5 activation is essential for FAK activation and cytoskeletal reorganization during migration of endothelial cells [78]. The exact mechanism for MK5-mediated FAK phosphorylation and activation remains to be solved.

A siRNA screen against the complete human kinome revealed an increase in c-MYC protein levels in cells treated with MK5 siRNA [82]. The authors went on to show that MK5 induced expression of the microRNAs miR-34b and miR-34c by phosphorylating the transcription factor FOXO3a which binds the pre-miR-34 promoter. MK5 predominantly phosphorylates FOXO3a at Ser-215 in vivo (and at other sites in vitro as well) and MK5-mediated phosphorylation of this site is required for the upregulation of miR-34b/c levels. The miR-34b/c binds c-myc mRNA, resulting in reduced c-MYC protein levels. MYC protein seems to be engaged in a negative feedback loop by binding to the MK5 promoter and enhancing expression of MK5 [82]. Because MYC is a central regulator of the cell cycle and aberrant MYC expression plays a central role in oncogenesis [83], Kress and colleagues investigated the state of MK5 expression in tumour cells with increased MYC levels. MK5 expression was higher in normal colon mucosa than in colorectal carcinoma, whereas MYC expression was weak in normal colon epithelium, but strong in colorectal tumour tissues. Moreover, low levels of MK5 mRNA were associated with increased probability of the development of distant metastasis [82]. These exciting findings point to a tumour-suppressive function of MK5. It would be interesting to validate the MK5-MYC link in mk5−/− mice or in transgenic mice overexpressing an active MK5 mutant by examining Myc levels and the development of colon cancer in these animals compared to wild-type mice. FOXO3a was recently shown to repress the VEGF promoter and reduce expression of VEGF [84]. FOXO3a also stimulates expression of miR34b, a microRNA that causes cell cycle G1 arrest and suppresses cell invasion of melanoma cells [85,86]. Hence, MK5 may through FOXO3a-mediated phosphorylation promote angiogenesis by enhancing the expression of VEGF, but reduce invasiveness by upregulation of miR-34b.

Conclusions

In vitro studies and animal models demonstrate that the ERK3/4-MK5 pathway can participate in several processes that are dysregulated in cancer, including cell proliferation, cell motility, invasiveness, and angiogenesis. However, a bona fide role for ERK3, ERK4 and MK5 in human cancer remains to be elucidated. ERK3, ERK4 and MK5 seem to act downstream of the Ras/Raf pathway or to be implicated in the regulation of c-Myc expression. The rasraf and c-myc genes are amongst the most commonly mutated genes in cancer [58,87,88]. The lack of potent Ras and c-Myc inhibitors and the acquirement of drug resistance make ERK3, ERK4, and MK5 attractive targets for therapeutic drugs in tumours with perturbed RAS, RAF or c-MYC activity. ERK3 was upregulated in doxorubicin-resistent breast cancer MCF-7 cells and can be a potential target for anti-cancer drug development [89]. Because MK5 can operate as a tumour suppressor and a tumour promoter, drugs that hamper or augment MK5’s activity should be designed. Some selective MK5 inhibitors have been identified, but they have not been tested in clinical trials [90-92]. No MK5 activators to stimulate its tumour suppressor property are available, nor have any compounds that modulate the activity of ERK3 and ERK4 been developed.

Abbreviations

DMBA, 7,12-dimethylbenzathracene; ERK, Extracellular signal-regulated kinase; IGF2BP1, Insulin-like growth factor 2 mRNA-binding protein 1; MAPK, Mitogen-activated protein kinase; MAPKAPK, MAPK-activated protein kinases; PRAK, p38 regulated/activated protein kinase; VEGF, Vascular endothelial growth factor; VEGFR2, VEGF receptor 2.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SK, GD, and UM contributed in drafting the manuscript and revising its scientific content. All authors read and approved the final manuscript.

Acknowledgements

Work in our lab is supported by grants from the Norwegian Cancer Society, Mohn foundation, Odd Berg Foundation, and Helse Nord (ID5025). SK receives a post doc from the Mohn foundation, while GD is financed by the Norwegian Cancer Society.

References

  1. Johnson GL, Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases.

    Science 2002, 298:1911-1912. PubMed Abstract | Publisher Full Text OpenURL

  2. Imajo M, Tsuchiya Y, Nishida E: Regulatory mechanisms and functions of MAP kinase signaling pathways.

    IUBMB Life 2006, 58:312-317. PubMed Abstract | Publisher Full Text OpenURL

  3. Zhang Y, Dong C: Regulatory mechanisms of mitogen-activated kinase signaling.

    Cell Mol Life Sci 2007, 64:2771-2789. PubMed Abstract | Publisher Full Text OpenURL

  4. Krishna M, Narang H: The complexity of mitogen-activated protein kinases (MAPKs) made simple.

    Cell Mol Life Sci 2008, 65:3525-3544. PubMed Abstract | Publisher Full Text OpenURL

  5. Cargnello M, Roux PP: Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.

    Microbiol Mol Biol Rev 2011, 75:50-83. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  6. Gaestel M: MAPKAP kinases - MKs - two's company, three's a crowd.

    Nat Rev Mol Cell Biol 2006, 7:120-130. PubMed Abstract | Publisher Full Text OpenURL

  7. Arthur JS: MSK activation and physiological roles.

    Front Biosci 2008, 13:5866-5879. PubMed Abstract | Publisher Full Text OpenURL

  8. Buxade M, Parra-Palau JL, Proud CG: The Mnks: MAPK kinase-interacting kinases (MAP kinase signal-integrating kinases).

    Front Biosci 2008, 13:5359-5373. PubMed Abstract | Publisher Full Text OpenURL

  9. Carriere A, Ray H, Blenis J, Roux PP: The RSK factors of activating the Ras/MAPK signaling cascade.

    Front Biosci 2008, 13:4258-4275. PubMed Abstract | Publisher Full Text OpenURL

  10. Vermeulen L, Vanden Berghe W, Beck IM, De Bosscher K, Haegeman G: The versatile role of MSKs in transcriptional regulation.

    Trends Biochem Sci 2009, 34:311-318. PubMed Abstract | Publisher Full Text OpenURL

  11. Raman M, Chen W, Cobb MH: Differential regulation and properties of MAPKs.

    Oncogene 2007, 26:3100-3112. PubMed Abstract | Publisher Full Text OpenURL

  12. Anjum R, Blenis J: The RSK family of kinases: emerging roles in cellular signalling.

    Nat Rev Mol Cell Biol 2008, 9:747-758. PubMed Abstract | Publisher Full Text OpenURL

  13. Romeo Y, Zhang X, Roux PP: Regulation and function of the RSK family of protein kinases.

    Biochem J 2012, 441:553-569. PubMed Abstract | Publisher Full Text OpenURL

  14. Gaestel M, Kotlyarov A, Kracht M: Targeting innate immunity protein kinase signalling in inflammation.

    Nature Rev Drug Discov 2009, 8:480-499. Publisher Full Text OpenURL

  15. Ronkina N, Kotlyarov A, Gaestel M: MK2 and MK3–a pair of isoenzymes?

    Front Biosci 2008, 13:5511-5521. PubMed Abstract | Publisher Full Text OpenURL

  16. Luig C, Köther K, Eva Dudek S, Gaestel M, Hiscott J, Wixler V, Ludwig S: MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR.

    FASEB J 2010, 24:4068-4077. PubMed Abstract | Publisher Full Text OpenURL

  17. Ronkina N, Kotlyarov A, Dittrich-Breiholz O, Kracht M, Hitti E, Milarski K, Askew R, Marusic S, Lin LL, Gaestel M, Telliez JB: The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK.

    Mol Cell Biol 2007, 27:170-181. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  18. Ehlting C, Ronkina N, Böhmer O, Albrecht U, Bode KA, Lang KS, Kotlyarov A, Radzioch D, Gaestel M, Häussinger D, Bode JG: Distinct functions of the mitogen-activated protein kinase-activated protein (MAPKAP) kinases MK2 and MK3: MK2 mediates lipopolysaccharide-induced signal transducers and activators of transcription 3 (STAT3) activation by preventing negative regulatory effects of MK3.

    J Biol Chem 2011, 286:24113-24124. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  19. Perander M, Keyse SM, Seternes OM: Does MK5 reconcile classical and atypical MAP kinases?

    Front Biosci 2008, 13:4617-4624. PubMed Abstract | Publisher Full Text OpenURL

  20. Aberg E, Perander M, Johansen B, Julien C, Meloche S, Keyse SM, Seternes OM: Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4.

    J Biol Chem 2006, 281:35499-35510. PubMed Abstract | Publisher Full Text OpenURL

  21. Kant S, Schumacher S, Singh MK, Kispert A, Kotlyarov A, Gaestel M: Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5.

    J Biol Chem 2006, 281:35511-35519. PubMed Abstract | Publisher Full Text OpenURL

  22. Coulombe P, Rodier G, Pelletier S, Pellerin J, Meloche S: Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation.

    Mol Cell Biol 2003, 23:4542-4558. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  23. Coulombe P, Rodier G, Bonneil E, Thibault P, Meloche S: N-terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome.

    Mol Cell Biol 2004, 24:6140-6150. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  24. Kostenko S, Shiryaev A, Gerits N, Dumitriu G, Klenow H, Johannessen M, Moens U: Serine residue 115 of MAPK activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function.

    Cell Mol Life Sci 2011, 68:847-862. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  25. De la Mota-Peynado A, Chernoff J, Beeser A: Identification of the atypical Erk3 as a novel substrate for p21-activated kinase (Pak) activity.

    J Biol Chem 2011, 286:13603-13611. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  26. Déléris P, Trost M, Topisirovic I, Tanguay PL, Borden KL, Thibault P, Meloche S: Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase signaling pathway.

    J Biol Chem 2011, 286:6470-6478. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  27. Klinger S, Turgeon B, Lévesque K, Wood GA, Aagaard-Tillery KM, Meloche S: Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality.

    Proc Natl Acad Sci USA 2009, 106:16710-16715. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  28. Rousseau J, Klinger S, Rachalski A, Turgeon B, Déléris P, Vigneault E, Poirier-Héon JF, Davoli MA, Mechawar N, El Mestikawy S, Cermakian N, Meloche S: Targeted inactivation of Mapk4 in mice reveals specific nonredundant functions of Erk3/Erk4 subfamily mitogen-activated protein kinases.

    Mol Cell Biol 2010, 30:5752-5763. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  29. Ni H, Wang XS, Diener K, Yao Z: MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase.

    Biochem Biophys Res Commun 1998, 243:492-496. PubMed Abstract | Publisher Full Text OpenURL

  30. New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J: PRAK, a novel protein kinase regulated by the p38 MAP kinase.

    EMBO J 1998, 17:3372-3384. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  31. Gerits N, Shiryaev A, Kostenko S, Klenow H, Shiryaeva O, Johannessen M, Moens U: The transcriptional regulation and cell-specific expression of the MAPK-activated protein kinase MK5.

    Cell Mol Biol Lett 2009, 14:548-574. PubMed Abstract | Publisher Full Text OpenURL

  32. Kostenko S, Dumitriu G, Lægreid KJ, Moens U: Physiological roles of mitogen-activated-protein-kinase activated p38-regulated/activated protein kinase.

    World J Biol Chem 2011, 2:73-89. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  33. Seternes OM, Johansen B, Hegge B, Johannessen M, Keyse SM, Moens U: Both binding and activation of p38 mitogen-activated protein kinase (MAPK) play essential roles in regulation of the nucleocytoplasmic distribution of MAPK-activated protein kinase 5 by cellular stress.

    Mol Cell Biol 2002, 22:6931-6945. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  34. Seternes OM, Mikalsen T, Johansen B, Michaelsen E, Armstrong CG, Morrice NA, Turgeon B, Meloche S, Moens U, Keyse SM: Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway.

    EMBO J 2004, 23:4780-4791. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  35. Schumacher S, Laass K, Kant S, Shi Y, Visel A, Gruber AD, Kotlyarov A, Gaestel M: Scaffolding by ERK3 regulates MK5 in development.

    EMBO J 2004, 23:4770-4779. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  36. Déléris P, Rousseau J, Coulombe P, Rodier G, Tanguay PL, Meloche S: Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4 is required for binding, activation and cytoplasmic relocalization of MK5.

    J Cell Physiol 2008, 217:778-788. PubMed Abstract | Publisher Full Text OpenURL

  37. Shiryaev A, Moens U: Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: ménage à trois or ménage à quatre?

    Cell Signal 2010, 22:1185-1192. PubMed Abstract | Publisher Full Text OpenURL

  38. Zheng M, Wang YH, Wu XN, Wu SQ, Lu BJ, Dong MQ, Zhang H, Sun P, Lin SC, Guan KL, Han J: Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy depletion-induced suppression of mTORC1.

    Nat Cell Biol 2011, 13:263-272. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  39. Gerits N, Mikalsen T, Kostenko S, Shiryaev A, Johannessen M, Moens U: Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5.

    J Biol Chem 2007, 282:37232-37243. PubMed Abstract | Publisher Full Text OpenURL

  40. Shi Y, Kotlyarov A, Laabeta K, Gruber AD, Butt E, Marcus K, Meyer HE, Friedrich A, Volk HD, Gaestel M: Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination.

    Mol Cell Biol 2003, 23:7732-7741. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  41. Gerits N, Van Belle W, Moens U: Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity.

    Behav Brain Funct 2007, 3:58. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  42. Julien C, Coulombe P, Meloche S: Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression.

    J Biol Chem 2003, 278:42615-42624. PubMed Abstract | Publisher Full Text OpenURL

  43. Tanguay PL, Rodier G, Meloche S: C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis.

    Biochem J 2010, 428:101-111. OpenURL

  44. Chen G, Hitomi M, Han J, Stacey W: The p38 pathway provides negative feedback for Ras proliferative signaling.

    J Biol Chem 2000, 275:38973-38980. PubMed Abstract | Publisher Full Text OpenURL

  45. Li Q, Zhang N, Zhang D, Wang Y, Lin T, Wang Y, Zhou H, Ye Z, Zhang F, Lin SC, Han J: Determinants that control the distinct subcellular localization of the p38α-PRAK and the p38β-PRAK complexes.

    J Biol Chem 2008, 283:11014-11023. PubMed Abstract | Publisher Full Text OpenURL

  46. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong MQ, Frangou CG, Yates JR, Wright PE, Han J: PRAK is essential for ras-induced senescence and tumor suppression.

    Cell 2007, 128:295-308. PubMed Abstract | Publisher Full Text OpenURL

  47. Gong X, Liu A, Ming X, Wang X, Wang X, Wang D, Deng P, Jiang Y: Effect of PRAK gene knockout on the proliferation of mouse embryonic fibroblasts.

    Front Med China 2009, 3:379-383. Publisher Full Text OpenURL

  48. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK: Somatic mutations affect key pathways in lung adenocarcinoma.

    Nature 2008, 455:1069-1075. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  49. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K, Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS, Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ, Faham M, Seshagiri S: Diverse somatic mutation patterns and pathway alterations in human cancers.

    Nature 2010, 466:869-873. PubMed Abstract | Publisher Full Text OpenURL

  50. Bell D, Berchuck A, Birrer M, Chien J, Cramer DW, Dao F, Dhir R, DiSaia P, Gabra H, Glenn P, Godwin AK, Gross J, Hartmann L, Huang M, Huntsman DG, Iacocca M, Imielinski M, Kalloger S, Karlan BY, Levine DA, Mills GB, Morrison C, Mutch D, Olvera N, Orsulic S, Park K, Petrelli N, Rabeno B, Rader JS, Sikic BI, Smith-McCune K, Sood AK, Bowtell D, Penny R, Testa JR, Chang K, Dinh HH, Drummond JA, Fowler G, Gunaratne P, Hawes AC, Kovar CL, Lewis LR, Morgan MB, Newsham IF, Santibanez J, Reid JG, Trevino LR, Wu YQ, Wang M, Muzny DM, Wheeler DA, Gibbs RA, Getz G, Lawrence MS, Cibulskis K, Sivachenko AY, Sougnez C, Voet D, Wilkinson J, Bloom T, Ardlie K, Fennell T, Baldwin J, Gabriel S, Lander ES, Ding LL, Fulton RS, Koboldt DC, McLellan MD, Wylie T, Walker J, O'Laughlin M, Dooling DJ, Fulton L, Abbott R, Dees ND, Zhang Q, Kandoth C, Wendl M, Schierding W, Shen D, Harris CC, Schmidt H, Kalicki J, Delehaunty KD, Fronick CC, Demeter R, Cook L, Wallis JW, Lin L, Magrini VJ, Hodges JS, Eldred JM, Smith SM, Pohl CS, Vandin F, Raphael BJ, Weinstock GM, Mardis ER, Wilson RK, Meyerson M, Winckler W, Getz G, Verhaak RG, Carter SL, Mermel CH, Saksena G, Nguyen H, Onofrio RC, Lawrence MS, Hubbard D, Gupta S, Crenshaw A, Ramos AH, Ardlie K, Chin L, Protopopov A, Zhang J, Kim TM, Perna I, Xiao Y, Zhang H, Ren G, Sathiamoorthy N, Park RW, Lee E, Park PJ, Kucherlapati R, Absher M, Waite L, Sherlock G, Brooks JD, Li JZ, Xu J, Myers RM, Laird PW, Cope L, Herman JG, Shen H, Weisenberger DJ, Noushmehr H, Pan F, Triche T, Berman BP, Van Den Berg DJ, Buckley J, Baylin SB, Spellman PT, Purdom E, Neuvial P, Bengtsson H, Jakkula LR, Durinck S, Han J, Dorton S, Marr H, Choi YG, Wang V, Wang NJ, Ngai J, Conboy JG, Parvin B, Feiler HS, Speed TP, Gray JW, Levine A, Socci ND, Liang Y, Taylor BS, Schultz N, Borsu L, Lash AE, Brennan C, Viale A, Sander C, Ladanyi M, Hoadley KA, Meng S, Du Y, Shi Y, Li L, Turman YJ, Zang D, Helms EB, Balu S, Zhou X, Wu J, Topal MD, Hayes DN, Perou CM, Getz G, Voet D, Saksena G, Zhang J, Zhang H, Wu CJ, Shukla S, Cibulskis K, Lawrence MS, Sivachenko A, Jing R, Park RW, Liu Y, Park PJ, Noble M, Chin L, Carter H, Kim D, Karchin R, Spellman PT, Purdom E, Neuvial P, Bengtsson H, Durinck S, Han J, Korkola JE, Heiser LM, Cho RJ, Hu Z, Parvin B, Speed TP, Gray JW, Schultz N, Cerami E, Taylor BS, Olshen A, Reva B, Antipin Y, Shen R, Mankoo P, Sheridan R, Ciriello G, Chang WK, Bernanke JA, Borsu L, Levine DA, Ladanyi M, Sander C, Haussler D, Benz CC, Stuart JM, Benz SC, Sanborn JZ, Vaske CJ, Zhu J, Szeto C, Scott GK, Yau C, Hoadley KA, Du Y, Balu S, Hayes DN, Perou CM, Wilkerson MD, Zhang N, Akbani R, Baggerly KA, Yung WK, Mills GB, Weinstein JN, Penny R, Shelton T, Grimm D, Hatfield M, Morris S, Yena P, Rhodes P, Sherman M, Paulauskis J, Millis S, Kahn A, Greene JM, Sfeir R, Jensen MA, Chen J, Whitmore J, Alonso S, Jordan J, Chu A, Zhang J, Barker A, Compton C, Eley G, Ferguson M, Fielding P, Gerhard DS, Myles R, Schaefer C, Mills Shaw KR, Vaught J, Vockley JB, Good PJ, Guyer MS, Ozenberger B, Peterson J, Thomson E: Integrated genomic analysis of ovarian carcinoma.

    Nature 2011, 474:609-615. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  51. Durinck S, Ho C, Wang NJ, Liao W, Jakkula LR, Collisson EA, Pons J, Chan SW, Lam ET, Chu C, Park K, Hong SW, Hur JS, Huh N, Neuhaus IM, Yu SS, Grekin RT, Mauro TM, Cleaver JE, Kwok PY, Leboit PE, Getz G, Cibulskis K, Aster JC, Huang H, Purdom E, Li J, Bolund L, Arron ST, Gray JW, Spellman PT, Cho RJ: Temporal dissection of tumorigenesis in primary cancers.

    Cancer Discov 2011, 1:137-143. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  52. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortés ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareño C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR: The mutational landscape of head and neck squamous cell carcinoma.

    Science 2011, 333:1157-1160. PubMed Abstract | Publisher Full Text OpenURL

  53. Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S, Comparative Sequencing Program NISC, Stemke-Hale K, Davies MA, Gershenwald JE, Robinson W, Robinson S, Rosenberg SA, Samuels Y: Exome sequencing identifies GRI2A as frequently mutated in melanoma.

    Nat Genet 2011, 43:442-446. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  54. Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Gosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Argo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA: Melanoma genome sequencing reveals frequent PREX2 mutations.

    Nature 2012, 485:502-506. PubMed Abstract | Publisher Full Text OpenURL

  55. Aberg E, Torgersen KM, Johansen B, Keyse SM, Seternes OM: Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif.

    J Biol Chem 2009, 284:19392-19401. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  56. Merkerova M, Bruchova H, Brdicka R: Expression analysis of PCNA gene in chronic myelogenous leukemia – combined application of siRNA silencing and expression arrays.

    Leukemia Res 2007, 31:661-672. Publisher Full Text OpenURL

  57. Rai R, Mahale A, Saranath D: Molecular cloning, isolation and characterization of ERK3 gene from chewing-tobacco induced oral squamous cell carcinoma.

    Oral Oncol 2004, 40:705-712. PubMed Abstract | Publisher Full Text OpenURL

  58. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA: Mutations of the BRAF gene in human cancer.

    Nature 2002, 417:949-954. PubMed Abstract | Publisher Full Text OpenURL

  59. Wellbrock C, Karasarides M, Marais R: The Raf proteins take centre stage.

    Nat Rev Mol Cell Biol 2004, 5:875-885. PubMed Abstract | Publisher Full Text OpenURL

  60. Hoeflich KP, Eby MT, Forrest WF, Gray DC, Tien JY, Stern HM, Murray LJ, Davis DP, Modrusan Z, Seghagiri S: Regulation of ERK3/MAPK6 expression by BRAF.

    Int J Oncol 2006, 29:839-849. PubMed Abstract | Publisher Full Text OpenURL

  61. Wang Q, Ding Q, Dong Z, Ehlers RA, Evers BM: Downregulation of mitogen-activated protein kinases in human colon cancers.

    Anticancer Res 2000, 20:75-83. PubMed Abstract OpenURL

  62. Liang B, Wang S, Zhu XG, Yu YX, Ciu ZR, Yu YZ: Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer.

    World J Gastroenterol 2005, 11:623-628. PubMed Abstract | Publisher Full Text OpenURL

  63. Makitie AA, Reis PP, Arora S, Macmillan C, Warner GC, Sukhai M, Dardick I, Perez-Ordonez B, Wells R, Brown D, Gilbert R, Freeman J, Gullane P, Irish J, Kamel-Reid S: Molecular characterization of salivary gland malignancy using Smgb-Tag transgenic mouse model.

    Lab Invest 2005, 85:947-961. PubMed Abstract | Publisher Full Text OpenURL

  64. Evtimova V, Schwirzke M, Tarbé N, Burtscher H, Jarsch M, Kaul S, Weidle UH: Identification of breast cancer metastasis-associated genes by chip technology.

    Anticancer Res 2001, 21:3799-3806. PubMed Abstract OpenURL

  65. Nambiar S, Mirmohammadsadegh A, Doroudi R, Gustrau A, Marini A, Roeder G, Ruzicka T, Hengge UR: Signaling networks in cutaneous melanoma metastasis identified by complementary DNA microarrays.

    Arch Dermatol 2005, 141:165-173. PubMed Abstract | Publisher Full Text OpenURL

  66. Long W, Foulds CE, Qin J, Liu J, Ding C, Lonard DM, Solis LM, Wistuba II, Qin J, Tsai SY, Tsai MJ, O’Malley BW: ERK3 signals through STC-3 coactivator to promote human lung cancer cell invasion.

    J Clin Invest 2012.

    pii: 61492 122:1869.1880.

    Publisher Full Text OpenURL

  67. Lee S, Kang J, Cho M, Seo E, Choi H, Kim E, Kim J, Kim H, Kang GY, Kim KP, Park YH, Yu DY, Yum YN, Park SN, Yoon DY: Profiling of transcripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omics approaches.

    Int J Oncol 2009, 34:161-172. PubMed Abstract | Publisher Full Text OpenURL

  68. Hansen CA, Bartek J, Jensen S: A functional link between the human cell cycle-regulatory phosphatase Cdc14A and the atypical mitogen-activated kinase Erk3.

    Cell Cycle 2008, 7:1-10. OpenURL

  69. Stöhr N, Köhn M, Lederer M, Glass M, Reinke C, Singer RH, Hüttelmaier S: IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling.

    Genes Dev 2012, 26:176-189. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  70. Yisraeli JK: VICKZ proteins: a multi-talented family of regulatory RNA-binding protein.

    Biol Cell 2005, 97:87-96. PubMed Abstract | Publisher Full Text OpenURL

  71. Mili S, Macara IG: RNA localization and polarity: from A(PC) to Z(BP).

    Trends Cell Biol 2009, 19:156-164. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  72. Vikensaa J, Hansen TV, Jonson L, Borup R, Wewer UM, Christiansen J, Nielsen FC: RNA-binding IMPs promote cell adhesion and invadopodia formation.

    EMBO J 2006, 25:1456-1468. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  73. Oberman F, Rand K, Maizels Y, Rubinstein AM, Yisraeli JK: VICKZ proteins mediate cell migration via their RNA binding activity.

    RNA 2007, 13:1558-1569. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  74. Vainer G, Vainer-Mosse E, Pikarsky A, Shenoy SM, Obermand F, Yeffet A, Singer RH, Pikarsky E, Yisraeli JK: A role for VICKZ proteins in the progression of colorectal carcinomas: regulating lamellipodia formation.

    J Pathol 2008, 215:445-456. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  75. Kostenko S, Moens U: Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology.

    Cell Mol Life Sci 2009, 66:3289-3307. PubMed Abstract | Publisher Full Text OpenURL

  76. Das M, Jiang F, SLuss HK, Zhang C, Shokat KM, Flavell RA, Davis RJ: Suppression of p53-dependent senescence by the JNK signal transduction pathway.

    Proc Natl Acad Sci USA 2007, 104:15759-15764. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  77. Wagner EF, Nebreda AR: Signal integration by JNK and p38 MAPK pathways in cancer development.

    Nat Rev Cancer 2009, 9:537-549. PubMed Abstract | Publisher Full Text OpenURL

  78. Yoshizuka N, Chen RM, Xu Z, Liao R, Hong L, Hi WY, Yu G, Han J, Chen L, Sun P: A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis.

    Mol Cell Biol 2012, 32:606-618. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  79. Rousseau S, Houle F, Landry J, Huot J: p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells.

    Oncogene 1997, 15:2169-2177. PubMed Abstract | Publisher Full Text OpenURL

  80. Shiryaev A, Dumitriu G, Moens U: Distinct roles of MK2 and MK5 in cAMP/PKA- and stress/p38MAPK-induced heat shock protein 27 phosphorylation.

    J Mol Signal 2011, 6:4. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  81. Zhao X, Guan JL: Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis.

    Adv Drug Deliv Rev 2011, 63:610-615. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  82. Kress TR, Cannell IG, Brenkman AB, Samans B, Gaestel M, Roepman P, Burgering BM, Bushell M, Rosenwald A, Eilers M: The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis.

    Mol Cell 2011, 41:445-457. PubMed Abstract | Publisher Full Text OpenURL

  83. Meyer N, Penn LZ: Reflecting on 25 years with MYC.

    Nat Rev Cancer 2008, 8:976-990. PubMed Abstract | Publisher Full Text OpenURL

  84. Karadedou CT, Gomes AR, Chen J, Petkovic M, Ho KK, Zwolinska AK, Feltes A, Wong SY, Chan KYK, Cheung YN, Tsang JWH, Brosens JJ, Khoo US, Lam EWF: FOXO3a represses VEGF expression through FOXM1-dependent and –independent mechanisms in breast cancer.

    Oncogene 2012, 31:1845-1858. PubMed Abstract | Publisher Full Text OpenURL

  85. Mazar J, Khaitan D, DeBlasio D, Zhong C, Govindarajan SS, Kopanathi S, Zhang S, Ray A, Perera RJ: Epigenetic regulation of microRNA genes and the role of miR-34b in cell invasion and motility in human melanoma.

    PLoS One 2011, 6:e24922. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  86. Dong F, Lou D: MicroRNA-34b/c suppresses uveal melanoma cell proliferation and migration through multiple targets.

    Mol Vision 2012, 18:537-546. OpenURL

  87. Prior IA, Lewis PD, Mattos C: A comprehensive survey of Ras mutations in cancer.

    Cancer Res 2012, 72:2457-2467. PubMed Abstract | Publisher Full Text OpenURL

  88. Albihn A, Johnsen JI, Henriksson MA: Myc in oncogenesis and as a target for cancer therapies.

    Adv Cancer Res 2010, 107:163-224. PubMed Abstract | Publisher Full Text OpenURL

  89. Yang JY, Ha SA, Yang YS, Kim JW: p-Glycoprotein ABCB5 and YB-1 expression plays a role in decreased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance.

    BMC Cancer 2010, 10:388. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  90. Kostenko S, Khan MT, Sylte I, Moens U: The diterpenoid alkaloid noroxoaconite is a Mapkap kinase 5 (MK5/PRAK) inhibitor.

    Cell Mol Life Sci 2011, 68:289-301. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  91. Anwar A, Hosoya T, Leong KM, Onogi H, Okuna Y, Hiramutsu T, Koyama H, Suzuki M, Hagiwara M, Garcia-Blanco MA: The kinase inhibitor SFV785 dislocates Dengue virus envelope protein from the replication complex and blocks virus assembly.

    PLoS One 2011, 8:e23246. OpenURL

  92. Andrew MJ, Clase JA, Bar G, Tricarico G, Edwards PJ, Brys R, Chambers M, Schmidt W, MacLeod A, Hirst K, Allen V, Birault V, Le J, Harris J, Self A, Nash K, Dixon G: Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis.

    Bioorg Med Chem Lett 2012, 22:2266-2270. PubMed Abstract | Publisher Full Text OpenURL