International Journal of Molecular Sciences Review Impact of ERK5 on the Hallmarks of Cancer Barbara Stecca 1,* and Elisabetta Rovida 2,* 1 Tumor Cell Biology Unit–Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), V. le Pieraccini 6, 50139 Florence, Italy 2 Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale G. B. Morgagni 50, 50134 Florence, Italy * Correspondence: [email protected] (B.S.); erovida@unifi.it (E.R.); Tel.: +39-055-7944567 (B.S.); +39-055-2751320 (E.R.) Received: 31 January 2019; Accepted: 18 March 2019; Published: 21 March 2019 Abstract: Extracellular signal-regulated kinase 5 (ERK5) belongs to the mitogen-activated protein kinase (MAPK) family that consists of highly conserved enzymes expressed in all eukaryotic cells and elicits several biological responses, including cell survival, proliferation, migration, and differentiation. In recent years, accumulating lines of evidence point to a relevant role of ERK5 in the onset and progression of several types of cancer. In particular, it has been reported that ERK5 is a key signaling molecule involved in almost all the biological features of cancer cells so that its targeting is emerging as a promising strategy to suppress tumor growth and spreading. Based on that, in this review, we pinpoint the hallmark-specific role of ERK5 in cancer in order to identify biological features that will potentially benefit from ERK5 targeting. Keywords: ERK5; BMK1; MAPK7; MEK5; cancer; cell proliferation; invasion; metastasis; apoptosis; targeted therapy 1. Introduction Extracellular signal-regulated kinase 5 (ERK5), the last mitogen-activated protein kinase (MAPK) family member discovered, is activated by the upstream kinase MEK5 in response to growth factors and stresses. While other MAPK members, such as ERK1/2, have well-established roles in tumorigenesis, the less-studied MEK5–ERK5 pathway has emerged as a pivotal player in cancer research only in the last few years. Accumulating evidence in preclinical models indicates the benefits of using MEK5–ERK5 inhibitory strategies for the treatment of human cancers and the contribution of MEK5–ERK5 signaling to therapy resistance. In this review, we summarize recent advances in the influence of ERK5 signaling on the 10 hallmarks of cancer drawn up by Hanahan and Weinberg [1]. 2. The ERK5 Signaling Pathway ERK5 (also referred to as big mitogen-activated protein kinase 1, BMK-1) is encoded by the MAPK7 gene and is a member of the MAPK family. ERK5 is ubiquitously expressed in mammalian tissues and cell types, where it is activated by extracellular stimuli, including several growth factors and cellular stresses [2–5]. Human ERK5 protein contains 816 amino acids and consists of an N-terminal kinase domain (78–406 aa) and a unique C-terminal tail (410–816 aa), which harbors an autoinhibitory function [6]. The C-terminus also contains a myocyte enhancer factor 2 (MEF-2)-interacting region (440–501 aa) [7], a nuclear localization signal (NLS) (505–539 aa), and a transcriptional activation domain (664–789 aa) [7], which associate with and activate several transcription factors [8]. Activation of ERK5 requires dual phosphorylation of threonine and tyrosine residues within a TEY motif in the activation loop of the kinase domain [9]. At this site, ERK5 can be phosphorylated and activated by Int. J. Mol. Sci. 2019, 20, 1426; doi:10.3390/ijms20061426 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 1426 2 of 21 Int.MEK5, J. Mol. whichSci. 2018 has, 19, x a FOR unique PEER specificity REVIEW for ERK5. Activation by MEK5 induces an open conformation2 of 21 of ERK5, the exposure of the NLS, and the translocation into the nucleus. The latter event is crucial thefor nucleus. the proliferative The latter signals event inducedis crucial by for ERK5 the pr [10oliferative]. Besides signals being phosphorylated induced by ERK5 at the[10]. TEY Besides motif, beingERK5 phosphorylated is able to phosphorylate at the TEY its motif, C-terminal ERK5 is tail able on to serine phosphorylate and threonine its C-terminal residues.These tail on residues serine andat thethreonine C-terminus residues. have alsoThese been residues reported at to the be phosphorylatedC-terminus have by also CDK1 been and/or reported ERK1/2 to [be11 ]. phosphorylatedUpstream activators by CDK1 of MEK5–ERK5 and/or ERK1/2 are [11]. MEKK2 Upstream and MEKK3, activators as well of MEK5–ERK5 as SRC [12], TPL2/COT,are MEKK2 and RAS, MEKK3,and AKT as [13 well]. Known as SRC substrates [12], TPL2/COT, for ERK5 areRAS, transcription and AKT factors,[13]. Known including substrates c-FOS, for c-MYC, ERK5 Sap-1a are transcriptionand MEF2A, factors, C and including D, and other c-FOS, kinases, c-MYC, such Sap-1a as RSK and and MEF2A, serum/glucocorticoid-regulated C and D, and other kinases,kinase such as(SGK) RSK and (Figure serum/glucocorticoid-regulated1)[14]. kinase (SGK) (Figure 1) [14]. Figure 1. Schematic representation of the MEK5–extracellular signal-regulated kinase 5 (ERK5) pathway Figure 1. Schematic representation of the MEK5–extracellular signal-regulated kinase 5 (ERK5) with activators and downstream effectors. pathway with activators and downstream effectors. 3. Sustaining Proliferative Signals 3. Sustaining Proliferative Signals ERK5 plays a well-established role in cell proliferation. Several reports have shown activation of ERK5ERK5 in response plays a well-established to several mitogens, role in including cell proliferation. epidermal Several growth reports factor have (EGF) shown [15], nerveactivation growth of ERK5factor in [16 response], fibroblast to several growth mitogens, factor (FGF) including [17], colony-stimulating epidermal growth factor-1 factor (EGF) [18], and[15], platelet-derived nerve growth factorgrowth [16], factor fibroblast (PDGF) growth [19]. factor ERK5 (FGF) regulates [17], differentcolony-stimulating phases of thefactor-1 cell cycle.[18], and For platelet-derived instance, ERK5 growthmediates factor G1/S (PDGF) transition [19]. byERK5 regulating regulates the different expression phases of cyclin of the D1. cell Conversely, cycle. For ERK5instance, inhibition ERK5 mediatesdecreases G1/S serum-induced transition by cyclin regulating D1 expression the expression [20]. Furthermore,of cyclin D1. Conversely, ERK5 is implicated ERK5 inhibition in G2/M decreasestransition serum-induced and is required forcyclin mitotic D1 entry.expression The induction [20]. Furthermore, of G2/M by ERK5 dependsis implicated on the in activation G2/M transitionof the transcription and is required factor for NF-kB, mitotic which entry. in The turn in upregulatesduction of G2/M mitosis-promoting by ERK5 depends genes, on suchthe activation as cyclins ofB1 the and transcription B2 and CDC25B factor [NF-kB,21,22]. which in turn upregulates mitosis-promoting genes, such as cyclins B1 andDuring B2 and the CDC25B last few [21,22]. years, several studies have demonstrated the critical role of MEK5–ERK5 signalingDuring in the cancer last few cell years, proliferation several andstudies tumorigenesis have demonstrated (Figure2 ).the The critical role role of ERK5 of MEK5–ERK5 in prostate signalingcancer (PC) in cancer proliferation cell proliferation is well established.and tumorigenesis Human (Figure PC displays 2). The role aberrant of ERK5 expression in prostate of cancer ERK5, (PC)with proliferation significant upregulation is well established. of ERK5 protein Human in high-gradePC displays tumors aberrant [23]. expression Increased ERK5 of ERK5, cytoplasmic with significantpositivity correlatesupregulation with of Gleason ERK5 protein score, bone in high-grade metastases, tumors and locally [23]. advancedIncreased diseaseERK5 cytoplasmic at diagnosis. positivityPointing correlates to an important with Gleason role of score, nuclear bone ERK5 metastases, in cancer, and a subgrouplocally advanced of PC patientsdisease at shows diagnosis. ERK5 Pointing to an important role of nuclear ERK5 in cancer, a subgroup of PC patients shows ERK5 nuclear localization, which correlates with poor disease survival [24]. Functionally, expression of a constitutively active form of MEK5 increases the percentage in the S phase of human PC LNCaP cells, leading to enhanced proliferation in vitro [23]. Along this line, overexpression of ERK5 in PC3 cells Int. J. Mol. Sci. 2019, 20, 1426 3 of 21 nuclear localization, which correlates with poor disease survival [24]. Functionally, expression of a constitutively active form of MEK5 increases the percentage in the S phase of human PC LNCaP cells, leading to enhanced proliferation in vitro [23]. Along this line, overexpression of ERK5 in PC3 cells increases proliferation in vitro and xenograft growth in vivo [24], whereas ERK5 silencing suppresses PC3 cell proliferation [25]. In addition, EGF-mediated ERK5 activation induces proliferation of RWPE-2 and PC3 cells by promoting entry into the S phase through upregulation of cyclins A and E [26]. Recently, phthalates have been shown to promote PC3 and 22RV1 PC cell proliferation through activation of ERK5 and p38, linking environmental pollution with ERK5 and cancer [27]. The role of microRNA as negative regulators of ERK5 is well documented and implicated in mediating ERK5-dependent PC cell proliferation. MiR-143 inversely correlates with nuclear ERK5 in human PC [28] and interferes with ERK5 signaling to abrogate PC progression in mice [29]. Similarly, overexpression of miR-143 suppresses proliferation