HGFR

HGF R, also known as Met (from N-methylN’ nitro-N-nitrosoguanidine induced), is a glycosylated receptor tyrosine kinase that plays a central role in epithelial morphogenesis and cancer development. HGF R is synthesized as a single chain precursor which undergoes co-translational proteolytic cleavage. This generates a mature HGF R that is a disulfide-linked dimer composed of a 50 kDa extracellular α chain and a 145 kDa transmembrane β chain. The extracellular domain (ECD) contains a seven bladed β-propeller sema domain, a cysteine-rich PSI/MRS, and four Ig-like E-set domains, while the cytoplasmic region includes the tyrosine kinase domain. Proteolysis and alternate splicing generate additional forms of human HGF R which either lack of the kinase domain, consist of secreted extracellular domains, or are deficient in proteolytic separation of the α and β chains. The sema domain, which is formed by both the α and β chains of HGF R, mediates both ligand binding and receptor dimerization. Ligand-induced tyrosine phosphorylation in the cytoplasmic region activates the kinase domain and provides docking sites for multiple SH2-containing molecules. HGF stimulation induces HGF R downregulation via internalization and proteasomedependent degradation. In the absence of ligand, HGF R forms noncovalent complexes with a variety of membrane proteins including CD44v6, CD151, EGF R, Fas, Integrin α6/β4, Plexins B1, 2, 3, and MSP R/Ron. Ligation of one complex component triggers activation of the other, followed by cooperative signaling effects. Formation of some of these heteromeric complexes is a requirement for epithelial cell morphogenesis and tumor cell invasion. Paracrine induction of epithelial cell scattering and branching tubulogenesis results from the stimulation of HGF R on undifferentiated epithelium by HGF released from neighboring mesenchymal cells. Genetic polymorphisms, chromosomal translocation, overexpression, and additional splicing and proteolytic cleavage of HGF R have been described in a wide range of cancers. Within the ECD, human HGF R shares 86-88% amino acid sequence identity with canine, mouse, and rat HGF R.