MODIFICATIONS OF THE HEPATOCYTE GROWTH-FACTOR C-MET PATHWAY BY CONSTITUTIVE EXPRESSION OF TRANSFORMING GROWTH-FACTOR-ALPHA IN RAT-LIVER EPITHELIAL-CELLS

We have previously shown that rat liver epithelial cells (RLEC) transf ected with and constitutively expressing transforming growth factor-al pha (TGF-alpha) have an enhanced mitogenic response to hepatocyte grow th factor (HGF). In the study reported here, we examined tumor clones derived from the TGF-alpha transfectants with respect to mitogenic res ponse to HGF. Tumor cell lines that expressed TGF-alpha responded to H GF with a greater increase in DNA synthesis than did the nontransfecte d parental RLEC (pRLEC). The tumor clones had also acquired a lower th reshold for HGF response, which enabled them to undergo significant DN A synthesis at a low concentration of HGF that did not evoke a respons e in the pRLEC or TGF-alpha transfectants. We investigated the mechani sms by which TGF-alpha expression may influence the HGF/c-met pathway. We showed that most TGF-alpha transfectants and tumor cells displayed increases in c-met mRNA and protein, indicating that the enhanced HGF response may be due in part to an increase in the amount of receptor present. However, in all transfectants and tumor clones that constitut ively expressed TGF-alpha, c-met was tyrosine phosphorylated in the ab sence of ligand (HGF) or other exogenous growth factors. These data su ggest that induction of c-met mRNA and transactivation of c-met may be a sequela of the constitutive expression of TGF-alpha and that consti tutive activation of the epidermal growth factor receptor pathway lead s to phosphorylation and activation of c-met. These studies provide ev idence for a novel mechanism of communication between epidermal growth factor receptor and c-met pathways that may partially explain the syn ergistic effects reported between TGF-alpha and HGF. Mel. Carcinog. 18 :244-255, 1997. (C) 1997 Wiley-Liss, Inc.