MET kinase (MET)

MET kinase, also known as Hepatocyte Growth Factor Receptor (HGFR), is a single-pass transmembrane protein and a receptor tyrosine kinase encoded by the MET gene. It serves as the receptor for hepatocyte growth factor (HGF). The protein undergoes proteolytic processing to form a mature disulfide-linked α/β heterodimer. Its structure includes an extracellular portion with Sema, PSI, Ig, and G-P repeat domains, and an intracellular portion with a juxtamembrane segment (containing regulatory phosphorylation sites), a tyrosine kinase domain (with key phosphorylation sites at Tyr1234 and Tyr1235), and a C-terminal region with a multisubstrate docking site (Tyr1349 and Tyr1356). Upon HGF binding, MET dimerizes, autophosphorylates, and activates its kinase activity, recruiting various adaptor and signaling molecules to trigger multiple downstream pathways including RAS-ERK, PI3K-AKT, PLCγ-PKC, STAT3, and NF-κB. MET signaling is crucial for diverse biological processes including cell proliferation, survival, motility, invasion, morphogenesis, angiogenesis, tissue homeostasis, and embryogenesis. Dysregulation of MET through overexpression, gene amplification, activating mutations, or increased ligand stimulation is implicated in the pathogenesis and progression of various cancers, contributing to increased tumor growth, metastasis, angiogenesis, and therapeutic resistance. Due to its critical role in cancer, MET has become a significant therapeutic target, with developed inhibitors like tepotinib and capmatinib showing efficacy in specific patient populations with MET alterations like exon 14 skipping mutations or amplification. MET is normally expressed in epithelial, endothelial, neuronal, and other cell types, while its ligand HGF is expressed by mesenchymal cells.

Other names

Hepatocyte Growth Factor ReceptorHGFR

Inhibition of MET kinase activity