HEPATOCYTE GROWTH-FACTOR (HGF) NK1 IS A NATURALLY-OCCURRING HGF SCATTER FACTOR VARIANT WITH PARTIAL AGONIST-ANTAGONIST ACTIVITY/

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proli feration, motility, and morphogenesis by activation of its receptor, t he c-Met tyrosine kinase. HGF/SF is structurally related to plasminoge n, including an amino-terminal hairpin loop, four kringle domains, and a serine protease-like region. A truncated HGF/SF isoform, designated HGF/NK2, which extends through the second kringle domain and behaves as a competitive HGF/SF antagonist, was previously shown to be encoded by an alternative HGF/SF transcript. In this study, we describe a sec ond naturally occurring HGF/SF variant, HGF/NK1, consisting of the HGF /SF amino-terminal sequence and first kringle domain. This product is encoded by a 2-kilobase alternative transcript containing intronic seq uence that was contiguous with exon K1b. Analysis of baculovirus-expre ssed HGF/NR1 revealed that this isoform possesses the heparin binding properties of HGF/SF and modest mitogenic and scattering activity rela tive to HGF/SF. However, at a 40-fold molar excess, HGF/NK1 inhibited HGF/SF-dependent DNA synthesis. HGF/NK1 stimulated tyrosine phosphoryl ation of Met, and covalent affinity crosslinking demonstrated a direct HGF/NK1-receptor interaction. These findings establish that the HGF/S F gene encodes multiple alternative products, which include not only a mitogenic agonist (HGF/SF) and a pure antagonist (HGF/NK2) but also a molecule with partial agonist/antagonist properties.