ACTIVATION OF C-SRC BY RECEPTOR TYROSINE KINASES IN HUMAN COLON-CANCER CELLS WITH HIGH METASTATIC POTENTIAL

Recent data suggest that signal transduction may have a critical role in the development and regulation of the metastatic phenotype. Here, w e investigated the role of c-Src activation in the process of human co lon cancer metastasis to the Liver, Our data, derived from two differe nt sets of human colon cancer cell line metastatic variants, suggest t hat not only do highly-metastatic cells display constitutively elevate d c-Src protein kinase activity when compared to poorly metastatic cel ls, but also that receptor tyrosine kinases participate in the ligand- activation of c-Src above basal levels. Specifically, the epidermal gr owth factor receptor (EGFR), p185HER2/Neu and the hepatocyte growth fa ctor receptor (c-Met) appear to be Linked to the process because they preferentially activate c-Src in highly-metastatic cells, EGFR was fou nd to associate with c-Src in colon cancer cells and specific inhibito rs of the EGFR resulted in a reduction of c-Src activity to basal leve ls. In addition, c-Src transfectants displayed partially-activated EGF Rs, suggesting a feedback role for c-Src in the regulation of the EGFR . p185HER2/Neu was also identified in immunocomplexes of c-Src followi ng Ligand activation of the EGFR, but only in highly-metastatic cells, Collectively, these observations suggest a paradigm whereby c-Src int eracts with multiple cell-surface growth factors in a catalytic fashio n for the development of tumor cells with metastatic potential.