Definition

Hepatocyte growth factor receptor (HGFR, AUTS9, DA11, DFNB97, RCCP2), also known as tyrosine-protein kinase Met or c-Met, is a protein encoded by the MET gene in humans. This protein has tyrosine kinase activity. Primary single-stranded precursor proteins are cleaved after translation to produce α and β subunits, which are linked by disulfide bonds to form mature receptors.

HGFR is a single-pass tyrosine kinase receptor that is essential for embryonic development, organogenesis, and wound healing. Hepatocyte growth factor/dispersion factor (HGF/SF) and its splicing subtypes (NK1, NK2) are the only known ligands for the HGFR receptor. HGFR is typically expressed by epithelial-derived cells, while expression of HGF/SF is limited to mesenchymal-derived cells. When HGF/SF binds to its homologous receptor HGFR, HGF/SF induces its dimerization through a mechanism that is not fully understood, leading to its activation. It induces its dimerization through a mechanism that is not fully understood, leading to its activation. Abnormal HGFR activation in cancer is associated with a poor prognosis, with abnormally active HGFR triggering tumor growth, the formation of new blood vessels that provide nutrients to the tumor (angiogenesis), and the spread of the cancer to other organs (metastasis). HGFR is unregulated in many types of human malignancies, including kidney, liver, stomach, breast, and brain cancers. Typically, only stem and progenitor cells express HGFR, which enables these cells to grow aggressively in order to produce new tissue in embryos or regenerate damaged tissue in adults. However, cancer stem cells are thought to hijack the ability of normal stem cells to express HGFR, thus becoming the reason why cancer persists and spreads to other parts of the body. Overexpression of Met/HGFR and autocrine activation caused by co-expression of hepatocyte growth factor ligands are associated with tumorigenesis.

Fig. 1 Schematic Structure of MET Protein

Signaling Pathway

Ligand HGF activation of the MET induces MET kinase catalytic activity, triggering transphosphorylation of tyrosine Tyr 1234 and Tyr 1235. These two tyrosines bind to various signal transductors to initiate METs-driven full-spectrum biological activity, collectively referred to as invasive growth processes. The sensor interacts directly with intracellular multisubstrate docking sites of the MET, such as the p85 regulatory subunit of GRB2, SHC, SRC, and phosphatidylinositol 3 kinase (PI3K), or indirectly through the scaffold protein Gab1.

Tyr 1349 and Tyr 1356 at multiple substrate docking sites are involved in interactions with GAB1, SRC, and SHC, while only Tyr 1356 is involved in the recruitment of GRB2, phospholipase C γ (PLC-γ), p85, and SHP2.

GAB1 is a key coordinator of the cellular response to MET and binds to MET intracellular regions with high affinity but low affinity. After interacting with the MET, GAB1 phosphorylates on several tyrosine residues, which in turn recruits many signaling effectors, including PI3K, SHP2, and PLC-γ. MET phosphorylation of GAB1 produces a sustained signal that mediates most downstream signaling pathways.

Fig. 2 HGFR Signaling Complex

Activation of Signal Transduction

HGFR is involved in activating several signal transduction pathways:

The RAS pathway mediates HGF-induced scattering and proliferation signals, leading to branching morphogenesis. Of note, unlike most mitogens, HGF induces sustained RAS activation, thereby prolonging MAPK activity.

The PI3K pathway is activated in two ways: PI3K can be located downstream of the RAS or recruited directly through the multifunctional docking site. Activation of the PI3K pathway is currently associated with cell motility through remodeling with adhesion to the extracellular matrix and local recruitment of transducers involved in cytoskeletal reorganization, such as RAC1 and PAK. PI3K activation also triggers a survival signal due to the activation of the AKT path.

STAT pathway and sustained MAPK activation are required for HGF-induced cladistic morphogenesis. MET directly activates the STAT3 transcription factor via the SH2 domain.

β The -catenin pathway, a key component of the Wnt signaling pathway, translocates into the nucleus after MET activation and is involved in the transcriptional regulation of many genes.

Notch pathway, activated by transcription of Delta ligands.

Clinical Application

Application in Cancer

The MET pathway plays an important role in the development of cancer by:

-- Activation of key carcinogenic pathways (RAS, PI3K, STAT3, β-catenin);

-- Angiogenesis (the growth of new blood vessels from existing blood vessels to provide nutrients for the tumor);

-- Dispersion (cell dissociation due to the production of metalloproteases), which often leads to metastasis.

-- miR-199a* coordinates downregulation of MET and its downstream effector extracellular signal-regulating kinase 2 (ERK2), which not only effectively inhibits cell proliferation, but also effectively inhibits the motility and invasion capacity of tumor cells.

MET amplification has emerged as a potential biomarker for clear cell tumor subtypes. Amplification of cell surface receptor MET often leads to colorectal cancer resistance to anti-EGFR therapy.

Application in Autism

The role of receptors in brain development is different from their role in other developmental processes. Activation of MET receptors regulates synaptic formation and can affect the development and function of circuits involved in social and emotional behavior. Thus, there are implications for autism and schizophrenia.

Application in Cardiac Function

In injured hearts, the HGF/MET axis plays an important role in cardiac protection by promoting the pro-survival (anti-apoptotic and anti-autophagy) effects of cardiomyocytes, angiogenesis, inhibition of fibrotic, anti-inflammatory, and immunomodulatory signals, and regeneration by activating cardiac stem cells.

Alpha Lifetech Inc. is dedicated to developing HGF receptor diagnostic regents. Alpha Lifetech Inc. is a reputable supplier focusing on research, manufacture and sales of In Vitro Diagnostic (IVD) regents. All the IVD regents offered by Alpha Lifetech Inc. have undergone strict QC validation and are certified by the COA (certificate of analysis). Meanwhile, we can provide customized services according to customers' requirements. Alpha Lifetech Inc. is committed to supplying high-quality, high-sensitivity antigen and antibody products for scientific research and industrial customers. In addition to regular small packages, Alpha Lifetech Inc.'s large-scale fermentation platform also allows us to provide raw material-grade IVD regents for the majority of industrial customers.

Please feel free to call our sales manager for technical information and a quotation!