The receptor for HGF was identified as a product of the c-met protooncogene in 1991. It consists of a 50-kDa α-subunit and a 145-kDa β-subunit, which are linked by a disulfide bond. The -subunit is completely extracellular, whereas the -subunit includes (from N to C termini) an extracellular region, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The mature heterodimeric receptor is generated by proteolytic processing and terminal glycosylation from a 170-kDa single-chain precursor. The HGFα-chain is as a high-affinity binding module to Met receptor, whereas theβ-chain is an activation module for Met. The binding of active HGF to the Met receptor induces activation of Met tyrosine kinase and the autophosphorylation of tyrosine residues in Met. Binding of HGF to c-Met induces phosphorylation of C-terminally clustered tyrosine residues of tyrosine kinase, which results in biological activities in a wide variety of cells, including mitogenic, motogenic and morphogenic activities. HGF/Met signaling activates multiple signal transduction pathways, including the Src/focal adhesion kinase (FAK) pathway, the p120/signal transducer and activator of transcription (STAT) 3 pathway, the phosphoinositide-3 kinase (PI3K)/Akt pathway, and the Ras/MEK pathway.
Besides Met, HGF has low-affinity/high-capacity binding sites corresponding to extracellular matrix molecules (glycosaminoglycans, or collagen) or to cell surface–associated heparan sulfate; this creates a molecular reservoir of HGF on the cell surface, whereas HGF transfer to Met initiates the cellular response. Recently, the mannose receptor has been identified as a receptor for the HGF β-chain, allowing for enhanced macrophage phagocytosis and, possibly, enhanced clearance of apoptotic neutrophils, which is associated with resolution of inflammation in the injured lung.