Role of c-MET Signaling in Cancer
Figure. c-MET receptor tyrosine kinases (RTKs) activated via hepatocyte growth factor (HGF) binding can result in multiple downstream effects conducive to cancerous cells. This figure illustrates the ways in which activated c-MET RTKs can recruit a variety of proteins such as GRB2, GAB1, PLCγ, SRC, and SHP2, and signal numerous pathways.
Adapted from Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010;16(1); 37-45.
It has been just over a quarter of a century since the discovery of the MET receptor and its ligand, hepatocyte growth factor (HGF). During this time, this signaling network has emerged as an important target for cancer therapy, with a particularly significant role in controlling the cancer hallmarks of metastasis and angiogenesis. Research has yielded a veritable bounty of potential therapies targeting this pathway, many of which are now entering the early stages of clinical trials, with a handful progressing into the later stages of development.
MET Receptor Signaling
Discovered in the mid-1980s, c-MET
is a proto-oncogene (a normal gene that, under certain circumstances, has the potential to become a cancer-causing oncogene). The protein encoded by the c-MET
gene is a cell surface receptor known as the mesenchymal epithelial transition factor, or MET receptor.
As with many other cell surface receptors discussed in the “Pathways” series, such as the epidermal growth factor receptor (EGFR), the MET receptor belongs to the receptor tyrosine kinase (RTK) family. This means that upon activation by a ligand, two receptor molecules pair up (dimerization), which activates the tyrosine kinase activity of the receptor and leads to its phosphorylation. The phosphorylated regions of the receptor act as binding sites for a range of signal transduction proproteins. HGF is the only known ligand for the MET receptor, and, as a result, the receptor is also often referred to as the HGF receptor (HGFR).
Among the many important signaling cascades induced by MET receptor activation are the phosphatidylinositol-3-kinase (PI3K)/Akt and the RAS/mitogen-activated protein kinase (MAPK) pathways. Furthermore, there is a substantial amount of cross-talk and interaction between the MET receptor pathway and those of the EGFR, vascular endothelial growth factor receptor (VEGFR), and beta-catenin/Wnt pathways.
A Tightly Controlled Pathway
The biological responses induced by the MET receptor pathway include cell proliferation and survival. However, MET receptor signaling plays a particularly important role in coordinating cell motility, invasion, and angiogenesis (the formation of new blood vessels), and plays a very active part in the development of the embryo and in the formation of organs during early human development.
In adults, activation of the MET receptor pathway is much more tightly regulated. MET receptor is predominantly expressed on cells of epithelial origin, while its ligand, HGF, is produced predominantly by mesenchymal cells. The MET receptor pathway is typically only switched on in adults in order to coordinate processes such as wound healing and tissue regeneration.
Given its important function in cell motility, invasion, and angiogenesis, it is unsurprising that cancer cells frequently hijack the MET receptor pathway to assist in the development of several hallmark capabilities. Abnormal MET expression is found in many different types of human malignancy, including kidney, liver, stomach, breast, and brain cancers, and it typically correlates with a poor prognosis. Among the multiple mechanisms of aberrant MET pathway activation is overexpression of the MET receptor or its ligand HGF and point mutations within the c-MET
In cancer cells, inappropriate activation of MET receptor signaling leads to a number of different biological outcomes that assist cancer development, which are collectively termed the invasive growth program. As part of this program, MET receptor activation promotes angiogenesis and aids in cancer cell invasion.
Furthermore, HGF is often referred to as scatter factor, since its activation of the MET receptor also enables cells to dissociate from one another and scatter. Finally, MET receptor signaling also drives the epithelial-to-mesenchymal transition (EMT; the conversion of cells from an epithelial phenotype to a more motile mesenchymal phenotype), which is an essential part of the ability of cancer cells to acquire the final hallmark of cancer, the ability to metastasize or spread to distant sites around the body.
For these reasons, both the MET receptor and HGF have emerged as key targets for cancer therapy.