We have begun characterizing the signal transduction pathways used by the c-met receptor in cells in which ligand (HGF-SF) stimulates motogenesis in the absence of mitogenesis. Primary targets (within 10-15 minutes) were identified as PI-3 kinase, GAP, PLC gamma, src, and MAP kinase, substrates which are also activated upon growth factor activation of mitogenic receptor systems. Following HGF-SF treatment, the 85 kD subunit of PI-3 kinase is phosphorylated on tyrosine and PI-3 kinase activity rapidly associates with the c-met receptor. A number of these substrates are implicated in cytoskeletal rearrangements and may be important in the motogenic response to the factor. We have also identified a number of colon carcinoma lines which express unamplified levels of constitutively tyrosine phosphorylated c-met protein. In these and other (gastric) cell lines which express amplified levels of activated receptor protein, we have determined that receptor activation is not due to the autocrine production of ligand.