The MAPK/ERK signalling pathway in cancer

Introduction

The mitogen-activated protein kinase (MAPK) signalling pathway is an important pathway in apoptosis, proliferation, differentiation, angiogenesis and metastasis. It is a protein kinase pathway (causes phosphorylation) with between 3-5 sets of kinases and is known to be activated via Ras, KC-mediated (Kupffer cells/liver macrophages), Ca2+, or G protein-coupled receptors. The MAPK/ERK pathway, also known as the Ras-Raf-MEK-ERK pathway, is conserved in mammals, and dysregulation of this pathway occurs in many different types of cancers. 

MAPK/ERK function

Ras (GTPase) activates Raf (serine/threonine kinase), which activates MEK1/2 (tyrosine & serine/threonine kinases) and ERK1/2 (serine/threonine kinases), which controls certain transcription factors. ERK1/2 also phosphorylates various substrates in the cytoplasm (not shown). This results in gene expression, which can cause apoptosis, cell cycle regulation, differentiation, proliferation, etc. (Fig. 1). It is estimated that there are more than 150 target substrates of ERK1/2, either directly or indirectly. Furthermore, Ras and RAF have several different subtypes which have different functions. Ras has four different subtypes, which are the GTPases: HRAS, KRAS4A/4B, and NRAS, with KRAS being the common form found in human cancers. RAF has subtypes, which are the kinases: ARAF, BRAF, and CRAF (in humans).  

Ras is activated when GRB2 (growth-factor-receptor bound protein 2) binds to SOS (son of sevenless). This occurs via the complex moving to the cell membrane upon activation of a transmembrane receptor, such as EGFR (epidermal growth factor receptor). SOS transports the signal from the receptor to RAS and aids in the conversion of RAS-GDP to RAS-GTP. This switches ‘on’ RAF, which leads to the phosphorylation of MEK and ERK (Fig. 1). ERK is then able to move into the nucleus and alter gene expression, of genes such as CREB, MYC, FOS, MSK, ELK, JUN, etc., which are involved in processes such as metabolism, proliferation, angiogenesis (formation of blood vessels), haematopoiesis (formation of blood cells), wound healing, differentiation, inflammation, and cancer. However, ERK is also able to activate other substrates in the cytoplasm, such as BIM, RSK, MNK, and MCL, which are involved in processes such as apoptosis and blood pressure regulation.  

A regular level of ERK expression is needed for activation of genes involved in the cell cycle and to inhibit negative cell cycle control. ERK phosphorylates Cyclin D and Cdk4/6, which are bound together and aid the cell in the movement from G1 (gap) to the S phase (DNA synthesis/repair) of the cell cycle. 

MAPK/ERK pathway in cancer

The MAPK/ERK pathway has been linked with many cancers, such as colon, thyroid, melanoma, pancreatic, lung, and glioblastoma. Mutations in epidermal growth factor receptor (EGFR), Ras, and Raf are well-known to cause cancer, with an estimated 33% of cancers containing Ras mutations, and an estimated 8% being caused by Raf mutations. It is also estimated that 85% of cancers have elevated activity of MEK. The MAPK/ERK pathway has also been shown to interact with the PI3K/Akt pathway, which controls the cell cycle and causes increased cell proliferation, which is obviously an important factor in tumourigenesis (tumour initiation).

Regulation of the MAPK/ERK pathway

There is a negative feedback mechanism of ERK1/2 on RAS/RAF/MEK, by ERK1/2 phosphorylating SOS, which causes the RAF-RAS link to be disrupted. ERK also inhibits MEK via the phosphorylation of BRAF and CRAF. There are inhibitors for Ras/Raf/MEK/ERK, but not all of these inhibitors work well/are without issues. ERK is problematic, in that their ATP-binding sites are very like cell cycle proteins, so are more difficult to inhibit. Also, it is difficult to target Ras due to its high GTP binding affinity, profuse cellular GTP, and lack of appropriate binding pockets. Therefore, the main focus currently appears to be on Raf/MEK inhibition. Raf inhibitors include drugs such as sorafenib, vemurafenib, encorafenib, and dabrafenib (these drugs are used on specific BRAF mutations). On the other hand, MEK inhibitors include drugs such as trametinib, cobimetinib, binimetinib, and selumetinib (these drugs can be used on specific mutations in Ras and Ras/Raf). 

Negative feedback mechanisms tightly control the MEK/ERK pathway and therefore great care is taken with inhibitor drug doses. To illustrate, if the doses are too low, the negative feedback loops are activated, which can lead to drug resistance/ poor therapeutic outcome. 

Conclusion

The MAPK/ERK pathway is essential for several cellular processes, such as apoptosis, cell cycle regulation, differentiation, and proliferation. Therefore, it has a critical role in tumourigenesis. Raf and MEK in particular are susceptible to inhibition, which has led to the production of several different drugs for use in various types of cancer. There are currently other clinical trials in progress, and these will hopefully lead to further therapies for other cancers involved in this pathway.

Written by Eleanor R Markham

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REFERENCES

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