MAPK/ERK pathway
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, including MAPK (mitogen-activated protein kinases, originally called ERK, extracellular signal-regulated kinases), which communicate by adding phosphate groups to a neighboring protein, which acts as an "on" or "off" switch. A range of cell-surface molecules activate RAS (KRAS, NRAS, and HRAS), a family of GTPases that act as molecular switches, turning on the downstream RAF protein kinases (BRAF, CRAF, and ARAF).
When one of the proteins in the pathway is mutated, it can become stuck in the "on" or "off" position, which is a necessary step in the development of many cancers. Components of the MAPK/ERK pathway were discovered when they were found in cancer cells. Drugs that reverse the "on" or "off" switch are being investigated as cancer treatments.
RAS Mutations
B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. This protein plays a role in regulating the Ras-Raf-MEK-ERK signaling pathway, which affects cell division, differentiation, and secretion.
Mutations in RAS proteins that lead to activation of RAF kinases are the most common oncogenes, present in approximately 30% of human cancers. Three million new cancers are diagnosed worldwide every year with RAS mutations. Mutated RAS proteins are also the most potent of human oncogenes, leading to changes that, along with other events, can transform normal cells into malignant cancer cells. RAS mutations are most frequent in pancreatic cancer (90%), colorectal cancer (40%), non–small cell lung cancer (30%), bladder cancer (30%), peritoneal cancer (30%), cholangiocarcinoma (25%), and melanoma (15%). Mutations in the RAF isoform BRAF, present in 6% of human cancers and responsible for approximately 500,000 new cancers per year, are also highly oncogenic in combination with other genetic events and capable of transforming normal cells to cancer cells.
It is no wonder that targeting RAS mutations has attracted the interest of the pharmaceutical industry.
Key components of the MAPK/ERK pathway. "P" represents phosphate, which communicates the signal. Top, epidermal growth factor (EGF) binds to the EGF receptor (EGFR) in the cell membrane, starting the cascade of signals. Further downstream, phosphate signal activates MAPK (also known as ERK). Bottom, signal enters the cell nucleus and causes transcription of DNA, which is then expressed as protein.
Targeting the RAS/RAF/MEK/ERK Pathway
BRAF inhibitors--Since constitutively active B-Raf mutants commonly cause cancer (see Clinical Significance) by excessively signaling cells to grow, inhibitors of B-Raf have been developed for both the inactive and active conformations of the kinase domain as cancer therapeutic candidates. Vemurafenib (Zelboraf) and dabrafenib (Tafinlar) are drugs attack the BRAF protein directly. These drugs shrink or slow the growth of tumors in some people whose metastatic melanoma has a BRAF gene change. They can also help some patients live longer, although the melanoma typically starts growing again eventually.
Readings and References
The MAP Kinase (MAPK) signalling pathway
The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity
Targeting RTK Signaling Pathways in Cancer
Exploring the Pathway: The RAS/RAF/MEK/ERK Pathway Fact Sheet