C-MET Receptor Tyrosine Kinase: A Potential Biomarker for Cancer Therapeutics

The c-MET/HGF signaling regulates multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. The c-MET pathway has significant interaction with other signaling pathways. The deregulation of c-MET plays an important role in the formation, growth, maintenance, and invasion of tumors. It is involved in various cancers, including lung, colon, liver and stomach cancer. Many studies on the abnormal signaling of c-MET offer strong reasons to investigate the therapeutic potential of some receptor antagonists.

Therefore, more active substances must be selected and integrated effectively into well-designed clinical trials; these include predictive biomarkers such as genetic mutation, amplification and overexpression of immunohistochemical c-MET. The complex interconnection of cell control networks provides new pathways for combining EGFR inhibitors and other targeted drugs. Thus, c-MET can be used as potential biomarkers for cancer therapeutics.

c-MET is a tyrosine kinase receptor in the MET family. Normally, it is expressed on the surfaces of several epithelial cells. HGF/SF is a common ligand for c-MET receptors. Cooper et al. were the first to identify the MET oncogene in 1984. They chemically transformed the human osteocarma cell line by transfection analysis in NIH/3T3 cells and mapped the MET oncogene. The MET oncogene was identified by the 7q21-31 chromosome band, showing a genetic shift between two different loci. MET’s proto-oncogenes are on chromosome 7 and on chromosome 1’s transfer promoter regions (TPRs). After analyzing the translation product of the proto-oncogene 21-exon MET proton, it was discovered on the surface of the cells and classified as a tyrosine kinase growth factor receptor.

The MET-proton-oncogene product acts as a receptor for the HGF tyrosine kinase transmembrane. The receptor is mainly present in melanocytes, epithelial cells and epithelial tissues, including the liver, the intestine, the kidneys and other organs. HGF regulates various transmission cascades on the c-MET receptor and acts on c-MET receptors in a paracrine manner (such as mitogenactivated protein kinase), phosphatidylinositol-3 kinase (PI3K)/AKT, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. The c-MET network consists of multiple signal molecules that interact with specific physiological processes. In addition to the properties of microbial, molecular, and morphological, c-MET protects against apoptosis by interactions with PI3K/AKT (phosphate di-tyrosine triphosphate/protein kinase-B). However, the co-expression of c-MET and HGF has been observed in various wound closure, tissue regeneration and embryonic events.

c-MET

c-MET is a receptor tyrosine kinase that is found primarily in melanocytes, endothelial cells and epithelial tissues such as the liver, gastrointestinal tract, and kidneys. In normal cells, primary MET transcripts produce 150 kDa peptides and partially glycosylated 170 kDa precursor proteins. Originally isolated from the line of human gastric tumor cells, the receptor contained a 50 kDa chain and a 145 kDa chain and was linked to a sulfur bridge in a transmembrane αβ complex of 190 kDa. 170 kDa precursor proteins are transformed by glycosylation and subsequent translation to produce mature heterodimers. The α-subunit is located on the outer layer, and the β-string, a single-pass chain, forms the core of the three main regions of the c-MET. The extracellular area of c-MET is highly adapted to HGF, while a single transmembrane segment and a cytoplasmic tyrosine kinase domain are cut by juxtamembrane and carboxyend sequences.

In the extracellular part, there are three types of domains. The SEMA domain, including 500 amino acids, is based on the α and β subunits in their entirety. The preserved c-MET receptor sequences are structurally similar to large families of ligand receptor pairs with semaphorin and plexin. Semaphorin is a large protein family that helps to decompose cells and induce reprehensible orientation events, such as cell dispersion during neural development. Under the SEMA domain, the PSI domain is a common domain for plexins, semaphorins, and integrins. It is connected to the transmembrane helix through four IPT domains (immunoglobulin-like, plexin-like, transcription factor). HGF can be connected to two locations in the SEMA area, one with a low specificity contact and a high specificity contact, and the other with a low specificity contact and a high affinity contact in the IPT region. The intracellular domain consists of three parts: the juxtamembrane sequence, which downregulates kinase activity, followed by Ser975 phosphorylation in the catalytic region for the activity of kinase leading to transphosphorylation of Tyr1234 and Tyr1235.

A dimerization of the receptors is caused by the phosphorylation of the tyrosine residues in the kinase domain. This may lead to the autophosphorylation of bidentate docking sites in the carbonate terminal tail of the cytoplasm (the Tyr1349 and Tyr1356 tyrosine residues). The total length of MET as a proto-oncogene is 125,982 bp and belongs to the 7q31 chromosome. HGF is a family of plasminogen-related growth factors known as PRGF-1. The length of the HGF gene spans 70 kb on chromosome 7q21.1. HGF, initially in the form of pro-HGF, is further cleaved by a protease to mature HGF.

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