Epidermal growth factor receptor signaling activates Met in human anaplastic thyroid carcinoma cells

Overexpression of Met is a common finding in thyroid carcinomas. Recently, we reported on overexpression and ligand-independent constitutive activatio n of Met in anaplastic thyroid carcinoma cells. In the present study we hav e investigated a putative mechanism for this phenomenon, Cell lines with co nstitutively activated Met expressed both TGF-alpha mRNA and protein. Weste rn blot analysis revealed expression of receptors for epidermal growth fact or (EGFR) in all carcinoma cell lines; in tumor cells with elevated levels of TGF-alpha mRNA there was a constitutive tyrosine phosphorylation of the EGFRs. Preincubation of carcinoma cells with suramin decreased EG;FR activa tion and downregulated Met expression as well as the ligand-independent pho sphorylation of Met. Similar results were obtained with a EGFR tyrosine kin ase inhibitor, AG 1478. The MEK inhibitor U0126 had an even more pronounced effect compared to AG 1478, indicating a Ras/MAPK-mediated signal in the r egulation of Met expression and activation, Inhibition of EGFR signaling al so decreased proliferation of the anaplastic thyroid carcinoma cells. Thus, aberrant activation of EGFRs may lead to an overexpression and activation of Met, which may be of importance for the malignant phenotype of anaplasti c thyroid carcinomas. (C) 2000 Academic Press.