Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering

A. Bardelli, C. Ponzetto, P. M. Comoglio

Research output: Contribution to journalArticlepeer-review


Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide which shares structural domains with enzymes of the blood clotting cascade. HGF/SF is secreted by cells of mesodermal origin and has powerful mitogenic, motogenic and morphogenic activity on epithelial and endothelial cells. HGF/SF is produced as a biologically inactive single-chain precursor (pro-HGF/SF) most of which is sequestered on the cell surface or bound to the extracellular matrix. Maturation into the active αβ heterodimer results from preteolytic cleavage by a urokinase-type protease, which acts as a pro-HGF/SF convertase. The primary determinant for receptor binding appears to be located within the α-chain. The interaction of the α-chain with the receptor is sufficient for the activation of the signal cascade involved in the motility response. However, the complete HGF/SF protein seems to be required to elicit a mitogenic response. HGF/SF binds with high affinity to a transmembrane receptor, p190MET, encoded by the MET proto-oncogene. p190MET is the prototype of a distinct subfamily of heterodimeric tyrosine kinases, including the putative receptors Ron and Sea. The mature form of p190MET is a heterodimer of two disulfide-linked subunits (α and β). The α-subunit is extracellular and heavily glycosylated. The β-subunit conssts of an extracellular portion involved in ligand binding, a membrane spanning segment, and a cytoplasmic tyrosine kinase domain. Both subunits derive from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. In polarized epithelial cells the HGF/SF receptor is selectively exposed in the basolateral plasmalemma, where it is associated with detergent-insoluble components. Two Met isoforms, carrying an intact ligand binding domain but lacking the kinase domain due to truncation of the β-subunit, arise from alternative post-transcriptional processing of the mature form. One truncated form is soluble and released from the cells. HGF/SF binding triggers tyrosine autophosphorylation of the receptor β-subunit. Autophosphorylation on the major phosphorylation site Y1235 upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. Negative regulation of the kinase activity occurs through phosphorylation of a unique serine residue (S985) located in the juxtamembrane domain of the receptor. This phosphorylation is triggered by two distinct pathways involving either protein kinase C activation or increase in intracellular Ca2+ concentration. Upon ligand binding, the HGF/SF receptor recruits and activates several cytoplasmic effectors, including phosphatidylinositol 3-kinase (PI 3-K), phospholipase C-γ (PLC-γ), pp60c-Src, a tyrosine phosphatase, and a Ras-guanine nucleotide exchanger. Interaction with these SH2 containing effectors is mediated by phosphorylation of a single multi-specific binding site, consisting of a pair of tyrosines (Y1349 and Y1356) located in the C-terminal tail of the HGF/SF receptor. Mutation of the two tyrosines results in loss of biological function, as shown by the abrogtion of the transforming activity in the oncogenic counterpart of the receptor.

Original languageEnglish
Pages (from-to)109-122
Number of pages14
JournalJournal of Biotechnology
Issue number2
Publication statusPublished - Sep 30 1994


  • HGF/SF
  • MET oncogenic
  • Signal transduction
  • Tyrosine kinase receptor

ASJC Scopus subject areas

  • Biotechnology


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