Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

SIMPLE SUMMARY: Alterations of the MEK5/ERK5 signaling pathway have been described in several tumors, and emerging data are trying to explain the complexity of ERK5-related mechanisms in both physiological and pathological conditions. Here, we provide an overview of the known evidence about ERK5 expression, activity, and regulation in tumors. Moreover, our study investigated the clinical significance and the prognostic value of ERK5 deregulation in human cancer. Upregulation and overexpression of ERK5 were reported in several tumor types associated with advanced stage, metastases, and worse overall survival. In addition, we focus on emerging insights regarding the relevance of ERK5 in a tumor-associated microenvironment. Finally, the recently discovered ERK5 isoforms, correlated with pro-tumoral function and negative regulation of ERK5, were also described. ABSTRACT: Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways.