| Hepatocyte Growth Factor (HGF) has been demonstrated to have mitogenic, scattering, and morphogenic influences on a number of cell types. The signal transducing receptor for HGF has been identified as the c-met protooncogene product, MET/HGFR, a receptor tyrosine kinase. MET/HGFR expression in a variety of cell types, predominantly epithelial in nature, suggests HGF may modulate growth of a number of tissues. Although well characterized in hepatocytes, the effects of HGF on normal non-hepatocyte epithelial cells has received less attention. This study investigates the effects of HGF on mouse epithelial cell lines derived from the mammary gland (M23), the kidney (MM55), and nonparenchymal liver epithelia (BNL CL.2 and NMuLi). These lines were selected randomly based upon a putative role for HGF in the tissue of origin, their commercial availability, and their designation as normal. HGF addition to M23 and MM55 cells induced DNA synthesis and mitogenesis only. However, addition of HGF to BNL CL.2 and NMuLi cells induced mitogenic, motogenic and morphogenic changes in these cells. HGF-inducible autophosphorylation of MET/HGFR was demonstrated in each of these cell lines. The role of several second messengers in the HGF-induced mitogenic response in M23 and MM55 cells was investigated, which demonstrated HGF-induced tyrosine phosphorylation and coprecipitation of the SH2 domain-containing proteins PI3-kinase, rasGAP, and NCK. HGF-induced increases in transcription of the early response genes c-fos, c-jun, junB, junD, and c-myc were also demonstrated. Furthermore, a role for PKC as a positive modulator of HGF-induced signals was confirmed. The role of autocrine HGF expression as a tumorigenic mechanism was also investigated in MM55, BNL CL.2 and NMuLi cells by transfecting the full length rat gene into these cells. The HGF-transfected BNL CL.2 and NMuLi cells, but not the MM55 cells, displayed many properties associated with transformation. These studies: (1) suggest that HGF may be important in the development and/or regeneration of breast, kidney and nonparenchymal liver epithelia; (2) have identified several possible mediators of HGF-induced mitogenesis; and (3) have implicated HGF in the tumorigenesis of at least some epithelial cells. |
