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Abstract
The importance of mitogen-activated protein kinases (MAPK) in human pathology is underlined by the relevance of abnormalities of MAPK-related signaling pathways to a number of different diseases, including inflammatory disorders and cancer. One of the key events in MAPK signaling, especially with respect to pro-proliferative effects that are crucial for the onset and progression of cancer, is MAPK nuclear translocation and its role in the regulation of gene expression. The extracellular signal-regulated kinase 5 (ERK5) is the most recently discovered classical MAPK and it is emerging as a possible target for cancer treatment. The bigger size of ERK5 when compared to other MAPK enables multiple levels of regulation of its expression and activity. In particular, the phosphorylation of kinase domain and C-terminus, as well as post-translational modifications and chaperone binding, are involved in ERK5 regulation. Likewise, different mechanisms control ERK5 nucleo-cytoplasmic shuttling, underscoring the key role of ERK5 in the nuclear compartment. In this review, we will focus on the mechanisms involved in ERK5 trafficking between cytoplasm and nucleus, and discuss how these processes might be exploited to design new strategies for cancer treatment.
Highlights
Protein phosphorylation is one of the key mechanisms used to transduce extracellular signals and transmit the information to the nucleus [1,2]
We recently reported that the overexpression of BRAFV600E in melanoma cells increases the nuclear amount of total and phosphorylated extracellular signal-regulated kinase 5 (ERK5) at S753 and T732, indicating that oncogenic BRAF, likely via extracellular signal-regulated kinases 1 and 2 (ERK1/2) and CDK1, enhances ERK5 functions as well as nuclear localization
We recently showed that five out of 479 melanoma patients harbor MAPK7 missense mutations, including P789S and A424S, two potential phosphorylation targets of C-terminus worth being characterized for their possible impact on ERK5 nuclear shuttling [88]
Summary
Protein phosphorylation is one of the key mechanisms used to transduce extracellular signals and transmit the information to the nucleus [1,2]. By tethering the MAPK to substrate, docking interactions contribute to the efficiency of kinase reaction [13,14] This kind of regulation enhances the complexity of the MAPK signaling cascade and is responsible for the tuning of the wide variety of functional effects of MAPK family. Another important feature of MAPK signaling is the large number of cascade substrates, which include transcription factors, protein kinases and phosphatases, components of cytoskeleton, regulators of apoptosis, and a variety of other signaling-related molecules. Many of these substrates are localized in the nucleus, where they are involved in the regulation of transcription, while others are in the cytosol or cytoplasmic organelles and are responsible for processes such as translation, mitosis, apoptosis and migration [6]
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