The MEK5/ERK5 Pathway in Health and Disease

Abstract

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.

Keywords: Krüppel-like factor; atherosclerosis; bone; cartilage; endothelium; extracellular-regulated kinase 5; mechanotransduction; mitogen-activated protein kinase; stress signaling; tumor.

Figure 1

Activation and function of the MEK5/ERK5 pathway in vascular endothelium. Laminar shear stress (LSS) induced by the steady blood flow through the vasculature results in phosphorylation of MEK5 in ECs, which subsequently phosphorylates ERK5 at a TEY-motif at threonine 219 and tyrosine 221 [9] (highlighted in red color). Subsequently, ERK5 autophosphorylates its C-terminus at multiple sites (including T733, shown as representative residue in dark orange) [20], leading to a change in conformation and nuclear localization of ERK5. Within the nucleus, ERK5 induces protective gene expression via transcriptional induction of the Krüppel-like factor 2 and 4 (KLF2/KLF4) transcription factors, thereby inhibiting apoptosis, inflammation, focal adhesion turnover, migration, and endothelial to mesenchymal transition (EndMT) [43,50,51,52,53]. Even though KLF2 and KLF4 can act functionally redundant in an overexpression situation, some functions may dominantly be controlled by only one of the two KLFs. For example, KLF2 induction alone is responsible for PAK1 repression, which contributes to the anti-migratory effect of ERK5 activation [51]. By contrast, BCAR1 suppression, which has been implicated in the inhibition of focal adhesion turnover [50] requires both KLF2 and KLF4 [51].

Figure 2

Laminar flow but not oscillatory flow activates the MEK5-ERK5-KLF axis: (a), phase contrast photographs of human umbilical vein endothelial cells (HUVEC) subjected to laminar shear stress (20 dyne/cm²) or oscillatory flow (2 Hz) for 120 h, as described [51,52]; (b), immunoblots of total cell lysates from the differently treated cells. Only laminar flow is able to induce ERK5 activation, as evident by appearance of a slower migrating band corresponding to C-terminally phosphorylated ERK5 [20], induction of KLF4 [43,49], the KLF2-target eNOS [53], and suppression of PAK1 [51] protein. Tubulin expression is shown as loading control.

Figure 3

Activation of ERK5 by drugs inhibiting the mevalonate pathway and correlation between CDC42 function and ERK5 activity: (a), 3-hydroxy-3-methylglutaryl-coenzym-A-reduktase inhibitors (statins), a group of cholesterol-lowering drugs, and N-bisphosphonates (N-BP), used for osteoporosis treatment, activate ERK5 via inhibition of the mevalonate biosynthesis pathway. By inhibition at different stages of the mevalonate cascade, both drugs interfere with prenylation and subsequent membrane localization of small GTPases such as CDC42, thus stalling them in a functionally inactive stage [71]. Functional inactivation of CDC42 leads to elevated ERK5 activity, which can be also mimicked by siRNA-mediated knockdown of CDC42 [73,74]. Activated ERK5 also inhibits PAK1 expression, thereby interfering with downstream effects of CDC42 [51]; (b), inverse correlation of ERK5 and CDC42 activity in mesenchymal stem cells (MSC) and differentiated osteoblasts. While ERK5 activity is high in MSCs, it drops during osteogenic differentiation [73,75]. Conversely, CDC42 activity is low in MSCs and rises during the differentiation process [73,76].

Figure 4

Tissue-sustaining effects of ERK5 in different mechanical stress-exposed tissues.

Figure 5

The MEK5/ERK5 pathway serves as an escape route to promote proliferation and survival of cancer cells under MAPKi. Oncogenic driver mutations in components of the RTK/RAS/RAF/MEK/ERK1/2 pathway lead to hyperactivation of the MEK/ERK1/2 cascade in multiple cancers. Existing inhibitors of the ERK1/2 pathway (MAPKi) targeting MEK1/2 (MEKi) or ERK1/2 (ERKi) trigger compensatory activation of the MEK5/ERK5 pathway via stimulation of different receptor tyrosine kinases (RTK) [37,119,120] in order to allow tumor cells to escape MAPKi-induced cell cycle arrest and apoptosis. Additionally, ERK5 activity appears to be upregulated by DUSP6 regulation, an ERK5 specific dual specificity phosphatase, whose inhibition by miR211 was shown to increase basal ERK5 phosphorylation [121].