HGF R, also known as Met (from N-methyl-N’-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 posttranslational proteolytic cleavage. This generates a mature HGF R that is a disulfide-linked dimer composed of a 50 kDa extracellular alpha chain and a 145 kDa transmembrane beta chain (1, 2). The extracellular domain (ECD) contains a seven bladed beta -propeller sema domain, a cysteine-rich PSI/MRS region, and four Ig-like E-set domains, while the cytoplasmic region includes a tyrosine kinase domain (3). The sema domain, which is formed by both the alpha and beta chains of HGF R, mediates both ligand binding and receptor dimerization (3, 4). Ligand-induced tyrosine phosphorylation in the cytoplasmic region activates the kinase domain and provides docking sites for multiple SH2-containing molecules (5, 6). HGF stimulation induces HGF R downregulation via internalization and proteasome-dependent degradation (7). In the absence of ligand, HGF R forms noncovalent complexes with a variety of membrane proteins including CD44v6, CD151, EGF R, Fas, integrin alpha 6/ beta 4, plexins B1, B2, and B3, and MSP R/Ron (8‑15). Ligation of one complex component triggers activation of the other, followed by cooperative signaling effects (8‑15). Formation of some of these heteromeric complexes is a requirement for epithelial cell morphogenesis and tumor cell invasion (8, 12, 13). HGF released from neighboring mesenchymal cells stimulates HGF R on undifferentiated epithelium and induces epithelial cell scattering and branching tubulogenesis (16). Genetic polymorphisms, chromosomal translocation, overexpression, and additional splicing and proteolytic cleavage of HGF R have been described in a wide range of cancers (1). Within the ECD, canine HGF R shares 85%‑88% amino acid sequence identity with human, mouse and rat HGF R.
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