HEPATOCYTE GROWTH FACTOR-INDUCED SCATTER OF MADIN-DARBY CANINE KIDNEY-CELLS REQUIRES PHOSPHATIDYLINOSITOL 3-KINASE

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine that induces mitogenesis, motility, invasion, and morphogenes is of several epithelial and endothelial cell lines in culture. The re ceptor for HGF/SF has been identified as the Met tyrosine kinase. To i nvestigate the signaling pathways that are involved in these events, w e have generated chimeric receptors containing the extracellular domai n of the colony stimulating factor-1 (CSF-1) receptor fused to the tra nsmembrane and intracellular domains of the Met receptor (MET). Madin- Darby canine kidney (MDCK) epithelial cells expressing the CSF-MET chi mera dissociate and scatter in response to CSF-1. However, cells expre ssing a mutant CSF-MET receptor containing a phenylalanine substitutio n for tyrosine 1356 were unable to scatter or form branching tubules f ollowing stimulation with CSF-1. Tyrosine 1356 is essential for the re cruitment of multiple substrates including the p85 subunit of PI3-kina se, phospholipase C gamma, and Grb2. In this study, we have investigat ed the role of PI3-kinase and a downstream target of PI3-kinase, pp70( S6K), in the induction of MDCK cell scatter in response to HGF/SF. Our results demonstrate that following stimulation with HGF/SF, activatio n of PI3-kinase but not pp70(S6K) is essential for MDCK cell scatter.