Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma. Signal transduction downstream HGF receptor (MET) activation involves multiple pathways that account for mitogenesis, motility and morphogenesis in a cell type-dependent fashion. MET receptor is aberrantly expressed in almost 100% of human osteosarcomas. We analyzed the effect of the MET receptor activation in five human osteosarcoma cell lines evaluating the levels of HGF-dependent activation of MAPK and PKB/AKT as biochemical readouts of mitogenic and invasive responses, respectively. All the cell lines tested expressed high levels of the MET proto-oncogene. Four cell lines showed activation of the MAPK cascade upon HGF stimulation, suggesting that this growth factor serves a common proliferative function in osteosarcomas. Two lines showed activation of PKB/AKT that is known to be involved in migration mediated by HGF receptor. Accordingly, cell lines where MAPK cascade was activated responded to HGF with increased proliferation, while induction and inhibition of PKB/AKT activity corresponded to acquisition or block of the invasive-motile response to HGF, respectively. Both the HGF dependent responses were reverted by the specific MET inhibitor K252a. These data show that HGF activates both the mitogen and motogen machinery in osteosarcoma cells and suggest that HGF might promote their malignant behavior by concomitant activation of different pathways and biological functions.