Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells

In rat liver epithelial cells constitutively expressing transforming growth factor alpha (TGF alpha), c-Met is constitutively phosphorylated in the ab sence of its ligand, hepatocyte growth factor. We proposed that TGF alpha a nd the autocrine activation of its receptor, epidermal growth factor recept or (EGFR), Leads to phosphorylation and activation of c-Met. We found that there is constitutive c-Met phosphorylation in human hepatoma cell lines an d the human epidermoid carcinoma cell line, A431 which express TGF alpha, b ut not in normal human hepatocytes, Constitutive c-Met phosphorylation in A 431, HepG2, AKN-1, and HuH6 cells was inhibited by neutralizing antibodies against TGFa and/or EGFR, Exposure to exogenous TGF alpha or EGF increased the phosphorylation of c-Met in the human epidermoid carcinoma cell line, A 431, The increase of c-Met phosphorylation by TGF alpha in A431 cells was i nhibited by neutralizing antibodies against TGF alpha and/or EGFR and by th e EGFR-specific inhibitor tyrphostin AG1478, These results indicate that co nstitutive c-Met phosphorylation, and the increase of c-Met phosphorylation by TGF alpha or EGF, in tumor cell lines is the result of the activation v ia EGFR, We found that c-Met in tumor cells co-immunoprecipitates with EGFR regardless of the existence of their ligands in tumor cells, but not in no rmal human hepatocytes. We conclude that c-Met associates with EGFR in tumo r cells, and this association facilitates the phosphorylation of c-Met in t he absence of hepatocyte growth factor. This cross-talk between c-Met and E GFR may have significant implications for altered growth control in tumorig enesis.