PLEIOTROPIC EFFECTS OF HEPATOCYTE GROWTH-FACTOR IN PROXIMAL TUBULE INVOLVE DIFFERENT SIGNALING PATHWAYS

Hepatocyte growth factor (HGF) accelerates renal tubule cell regenerat ion and induces tubulogenic differentiation via the intracellular tyro sine kinase (TK) domain of its receptor, the proto-oncogene c-Met. We tested whether different signaling pathways may be involved by examini ng HGF binding and effects on cell proliferation. migration, scatterin g, and tubulogenic differentiation in the bipolar differentiating rabb it proximal tubule cell line PT-1 under serum-free conditions in the p resence or absence of the protein TK inhibitors (PTKIs) herbimycin-A, genistein, methyl-2,5-dihydroxycinnamate, and geldanamycin. These PTKI s inhibit pp60(c-src), a nonreceptor TK involved in cell-growth contro l, HGF bound to a single high-affinity receptor class, increased micro villi numbers 1.5-fold, enhanced cell proliferation and migration 1.8- fold. and stimulated formation of tubule structures 2.2-fold. PTKI inh ibited the mitogenic and motogenic effects of HGF with different poten cies and comparable maximal effects but had no specific influence on H GF-induced tubulogenic cell differentiation. These data underline the importance of pp60(c-src) in mediating mitogenic and motogenic effects of HGF, whereas stimulation of tubulogenic cell differentiation may b e transduced by a pp60(c-src)- independent pathway.