The MEK5/ERK5 Pathway in Health and Disease
<p>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 [<a href="#B9-ijms-22-07594" class="html-bibr">9</a>] (highlighted in red color). Subsequently, ERK5 autophosphorylates its C-terminus at multiple sites (including T733, shown as representative residue in dark orange) [<a href="#B20-ijms-22-07594" class="html-bibr">20</a>], 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) [<a href="#B43-ijms-22-07594" class="html-bibr">43</a>,<a href="#B50-ijms-22-07594" class="html-bibr">50</a>,<a href="#B51-ijms-22-07594" class="html-bibr">51</a>,<a href="#B52-ijms-22-07594" class="html-bibr">52</a>,<a href="#B53-ijms-22-07594" class="html-bibr">53</a>]. 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 [<a href="#B51-ijms-22-07594" class="html-bibr">51</a>]. By contrast, BCAR1 suppression, which has been implicated in the inhibition of focal adhesion turnover [<a href="#B50-ijms-22-07594" class="html-bibr">50</a>] requires both KLF2 and KLF4 [<a href="#B51-ijms-22-07594" class="html-bibr">51</a>].</p> "> Figure 2
<p>Laminar flow but not oscillatory flow activates the MEK5-ERK5-KLF axis: (<b>a</b>), phase contrast photographs of human umbilical vein endothelial cells (HUVEC) subjected to laminar shear stress (20 dyne/cm<sup>2</sup>) or oscillatory flow (2 Hz) for 120 h, as described [<a href="#B51-ijms-22-07594" class="html-bibr">51</a>,<a href="#B52-ijms-22-07594" class="html-bibr">52</a>]; (<b>b</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 [<a href="#B20-ijms-22-07594" class="html-bibr">20</a>], induction of KLF4 [<a href="#B43-ijms-22-07594" class="html-bibr">43</a>,<a href="#B49-ijms-22-07594" class="html-bibr">49</a>], the KLF2-target eNOS [<a href="#B53-ijms-22-07594" class="html-bibr">53</a>], and suppression of PAK1 [<a href="#B51-ijms-22-07594" class="html-bibr">51</a>] protein. Tubulin expression is shown as loading control.</p> "> Figure 3
<p>Activation of ERK5 by drugs inhibiting the mevalonate pathway and correlation between CDC42 function and ERK5 activity: (<b>a</b>), 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 [<a href="#B71-ijms-22-07594" class="html-bibr">71</a>]. Functional inactivation of CDC42 leads to elevated ERK5 activity, which can be also mimicked by siRNA-mediated knockdown of <span class="html-italic">CDC42</span> [<a href="#B73-ijms-22-07594" class="html-bibr">73</a>,<a href="#B74-ijms-22-07594" class="html-bibr">74</a>]. Activated ERK5 also inhibits PAK1 expression, thereby interfering with downstream effects of CDC42 [<a href="#B51-ijms-22-07594" class="html-bibr">51</a>]; (<b>b</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 [<a href="#B73-ijms-22-07594" class="html-bibr">73</a>,<a href="#B75-ijms-22-07594" class="html-bibr">75</a>]. Conversely, CDC42 activity is low in MSCs and rises during the differentiation process [<a href="#B73-ijms-22-07594" class="html-bibr">73</a>,<a href="#B76-ijms-22-07594" class="html-bibr">76</a>].</p> "> Figure 4
<p>Tissue-sustaining effects of ERK5 in different mechanical stress-exposed tissues.</p> "> Figure 5
<p>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) [<a href="#B37-ijms-22-07594" class="html-bibr">37</a>,<a href="#B119-ijms-22-07594" class="html-bibr">119</a>,<a href="#B120-ijms-22-07594" class="html-bibr">120</a>] 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 [<a href="#B121-ijms-22-07594" class="html-bibr">121</a>].</p> ">
Abstract
:1. Introduction
2. The MEK5/ERK5 Pathway
2.1. ERK5: Structure and Regulation
2.2. ERK5 in Proliferation
2.3. Physiological Functions of the MEK5/ERK5 Pathway Revealed by Knockout Studies
3. ERK5 in Mechanical Stress-Exposed Tissues and MAPK Inhibitor-Resistant Cancers
3.1. Endothelium
3.2. Bone and Cartilage
3.3. Heart and Skeletal Muscle
3.4. ERK5 in Cancer
4. Manipulating ERK5—A Double-Edged Sword
Author Contributions
Funding
Conflicts of Interest
References
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Human ERK5 Peptide Position(s) 1 (Reference Peptide Sequence Uniprot Q13164) | Mouse Equivalent Position(s) (Reference Peptide Sequence Uniprot Q9WVS8) | Domain | Proposed Kinase(s) | Reference |
---|---|---|---|---|
T219 and Y221 | T219 and Y221 | KD 2 | MEK5 | [6] |
T733, S770, S774, and S776 | T723, S760, S764, and S766 | TAD | ERK5 (auto) | [20] |
T733, S770, S774, and S776 | T723, S760, S764, and S766 | TAD | ERK5 (auto) 3 | [23] |
T733 | T723 | TAD | CDK5 | [24] |
S707, T733, S754, and S774 | S697, T723, S744, and S764 | TAD | CDK1 4 | [25] |
S567, S720, S731, T733, and S803 | S567, S710, S721, T723, and S793 | TAD | CDK1 4 | [26] |
T733 | T733 | TAD | ERK2 4 | [23] |
Tumor Type | Employed Inhibitor Combinations In Vivo | Reference | |
---|---|---|---|
MAPKi | ERK5i | ||
BRAF mutant melanoma | Vemurafenib (BRAFi) + Trametinib (MEKi) | XMD8-92 | [123] |
BRAF mutant melanoma | Vemurafenib (BRAFi) | XMD8-92 | [124] |
NRAS mutant melanoma | Trametinib (MEKi) | XMD8-92 | [37] |
KRAS mutant non-small cell lung cancer | Cobimetinib (MEKi) | shERK5 | [125] |
KRAS mutant pancreatic ductal adenocarcinoma | SCH772984 (ERKi) | XMD8-92 | [120] |
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Paudel, R.; Fusi, L.; Schmidt, M. The MEK5/ERK5 Pathway in Health and Disease. Int. J. Mol. Sci. 2021, 22, 7594. https://doi.org/10.3390/ijms22147594
Paudel R, Fusi L, Schmidt M. The MEK5/ERK5 Pathway in Health and Disease. International Journal of Molecular Sciences. 2021; 22(14):7594. https://doi.org/10.3390/ijms22147594
Chicago/Turabian StylePaudel, Rupesh, Lorenza Fusi, and Marc Schmidt. 2021. "The MEK5/ERK5 Pathway in Health and Disease" International Journal of Molecular Sciences 22, no. 14: 7594. https://doi.org/10.3390/ijms22147594