Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

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.

Glucose Starvation or Pyruvate Dehydrogenase Activation Induce a Broad, ERK5-Mediated, Metabolic Remodeling Leading to Fatty Acid Oxidation

“…This effectively reduces ERK5 mRNA and protein between 30% and 70% in the different cell types used in this study [8,14,16], which we confirmed below in this study (see Figure 4E). As previously described, ERK5 has multiple functions, e.g., adaptor, transcriptional activator, kinase and differences on ERK5 levels can differently modulate its effects on the expression of its targets [17][18][19][20][21]. These decreases in expression were similar for MEF2 proteins, although the decrease was bigger for MEF2A than for MEF2C [8,14,16].…”

“…Other physiological effects of DCA are mediated by ERK5, also mainly through MEF2 activation [15,16]. Although ERK5 also has its own transcriptional domain, it translates stress signals, including metabolic stress, to gene expression through MEF2 [17][18][19][20][21]. ERK5 plays key roles multiple cellular functions [20], including on cell metabolism [22] and to some extent in the control of lipid metabolism [8,23,24].…”

“…Although ERK5 also has its own transcriptional domain, it translates stress signals, including metabolic stress, to gene expression through MEF2 [17][18][19][20][21]. ERK5 plays key roles multiple cellular functions [20], including on cell metabolism [22] and to some extent in the control of lipid metabolism [8,23,24]. This could explain the role of ERK5 in atherosclerosis [19,23,25,26], a disease in which cholesterol levels constitute a risk factor.…”

ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology

“…Finally, from a clinical point of view, our murine model opens a new window of therapeutic and diagnostic possibilities for sarcomatous pathologies based on ERK5-dependent signaling [ 24 ]. In this regard, the effectivity of ERK5 inhibitors in preclinical models has been shown [ 49 , 70 , 71 ].…”

“…In fact, ERK5, one of the canonical members of MAPKs superfamily described more than 25 years ago [ 20 , 21 ], is highly expressed in sarcomatous pathology, as indicated in The Cancer Genome Atlas (TCGA) series (see below). Interestingly, this particular MAPK signaling pathway has been linked to cancer [ 22 , 23 ], and it is expected to exploit its clinical implications in the coming years [ 24 ]. Indeed, ERK5 has been related to several types of tumors such as breast [ 25 ], multiple myeloma [ 26 ], or cholangiocarcinoma [ 27 ].…”