REVIEWS Drug Discovery Today  Volume 21, Number 10  October 2016 The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target Andre ´ E.S. Simo ˜ es, Cecı´lia M.P. Rodrigues 1 and Pedro M. Borralho 1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal Conventional mitogen-activated protein kinase (MAPK) family members are among the most sought- after oncogenic effectors for the development of novel human cancer treatment strategies. MEK5/ERK5 has been the less-studied MAPK subfamily, despite its increasingly demonstrated relevance in the growth, survival, and differentiation of normal cells. MEK5/ERK5 signalling has already been proposed to have pivotal roles in several cancer hallmarks, and to mediate the effects of a range of oncogenes. Accumulating evidence indicates the contribution of MEK5/ERK5 signalling to therapy resistance and the benefits of using MEK5/ERK5 inhibitory strategies in the treatment of human cancer. Here, we explore the major known contributions of MEK5/ERK5 signalling to the onset and progression of several types of cancer, and highlight the potential clinical relevance of targeting MEK5/ERK5 pathways. Introduction The MAPK family members regulate signal transduction cascades that are highly conserved among eukaryotes and are known to be involved in the control of several intracellular events, including proliferation, differentiation, migration, and apoptosis (reviewed in [1]). Thus far, four conventional and three atypical MAPK subfamilies have been identified. The four conventional MAPK subfamilies are: extracellular signal-regulated protein kinases 1/2 (ERK1/2); c-Jun N-terminal kinases 1–3 (JNK1, 2 and 3); p38 MAPKs (p38 a, b, g and d); and the most recently discovered ERK5. By contrast, ERK3/4, ERK7, and Nemo-like kinase (NLK) are consid- ered atypical MAPKs partly because their N- and C-terminal do- main extensions are not similar to, nor present in, conventional MAPKs. Despite the approximately 45% homology to convention- al MAPKs, the biological role of atypical MAPKs remains elusive [1]. Activation of conventional MAPK cascades is triggered by sev- eral stimuli, including internal metabolic stress, as well as by external mitogens, hormones, or neurotransmitters, cell–matrix and cell–cell interactions (reviewed in [2]). The well-stratified canonical activation of MAPK cascades proceeds through a three-tiered hierarchical module comprising a mitogen-activated kinase kinase kinase (MAPKKK) that phosphorylates mitogen-ac- tivated kinase kinase (MAPKK), which ultimately phosphorylates MAPK (reviewed in [3]) (Fig. 1). ERK5 identification ERK5, encoded by the MAPK7 gene, was first identified as big mitogen kinase 1 (BMK1) and cloned in two independent studies, two decades ago. It was found to be expressed in several tissues, being particularly abundant in heart, brain, lung, skeletal muscle, placenta, and kidney [4,5]. Structurally, ERK5 protein contains a N-terminal kinase domain with approximately 66% sequence homology with ERK1/2, and a unique and large C terminus that contains a transactivation domain, a nuclear localisation sequence (NLS), a nuclear export sequence (NES), and two proline-rich regions [4,6,7]. ERK5 activation occurs via dual phosphorylation of its N-terminal domain, prompted by active MEK5. Once active, ERK5 phosphorylates multiple sites in its C-terminal domain, enhancing its own transcriptional activity [8] (Fig. 2). In the unphosphorylated form, ERK5 presents an autoinhibitory mecha- nism, where its N- and C-terminal domains are bound. The acti- vation of ERK5 N-terminal kinase by MEK5 allows the phosphorylation of ERK5 substrates and the ERK5 C-terminal Reviews  GENE TO SCREEN Corresponding authors: Rodrigues, Cecı ´lia M.P. (cmprodrigues@ff.ulisboa.pt), Borralho, P.M. (borralhopm@gmail.com) 1 Senior authors. 1654 www.drugdiscoverytoday.com 1359-6446/ß 2016 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2016.06.010