C-Terminal Truncated Forms of Met, the Hepatocyte Growth Factor Receptor

Abstract

The MET proto-oncogene encodes a transmembrane tyrosine kinase of 190 kDa (p190^MET), which has recently been identified as the receptor for hepatocyte growth factor/scatter factor. p190^MET is a heterodimer composed of two disulfide-linked chains of 50 kDa (p50^α) and 145 kDa (pl45^β). We have produced four different monoclonal antibodies that are specific for the extracellular domain of the Met receptor. These antibodies immunoprecipitate with p190^MET two additional Met proteins of 140 and 130 kDa. The first protein (p140^MET) is membrane bound and is composed of an α chain (p50^α) and an 85-kDa C-terminal truncated β chain (ρ85^β). The second protein (p130^MET) is released in the culture supernatant and consists of an α chain (p50^α) and a 75-kDa C-terminal truncated β chain (p75^β). Both truncated forms lack the tyrosine kinase domain. p140^MET and p130^MET are consistently detected in vivo, together with p190^MET in different cell lines or their culture supernatants. p140^MET is preferentially localized at the cell surface, where it is present in roughly half the amount of p190^MET. The two C-terminal truncated forms of the Met receptor are also found in stable transfectants expressing the full-length MET cDNA, thus showing that they originate from posttranslational proteolysis. This process is regulated by protein kinase C activation. Together, these data suggest that the production of the C-terminal truncated Met forms may have a physiological role in modulating the Met receptor function.