Hepatocyte growth factor signal coupling to various transcription factors depends on triggering of Met receptor and protein kinase transducers in human hepatoma cells HepG2

Hepatocyte growth factor (HGF) regulates a wide variety of biological activ ities by binding to the tyrosine kinase receptor Met. In HGF-treated hepato carcinoma cells, we observed a biphasic activation of AP-1 and AP-2 transcr iption factors, For NF-kappa B complex the p50-p50 homodimer was activated before the p50-pG5 heterodimer, and c-Myc/Max DNA-binding activity increase d thereafter. Since these transcription factors are responders to mitogenic stimulation through protein kinase transducers, we tested the effects of i nhibitors of these enzymes on the DNA binding after HGF treatment. Inhibiti on of protein kinase C (PKC) with H7 strikingly activated NF-kappa B above the values observed after HGF alone. Under this inhibitory condition, Met t yrosine phosphorylation was elevated as though the phosphorylation-dependen t activity of the receptor was partially blocked by activation of PKC due t o HGF, NF-kappa B DNA binding seems to be related to Met triggering by HGF since it was largely prevented by genistein treatment, which blocks recepto r activity. Phosphatidylinositol 3-kinase seems to be involved in AP-1 bind ing activity stimulated by HGF. It is noteworthy that Met is responsive to HGF stimulating postreceptor signaling, which converges on the activation o f transcription factors acting coordinately to regulate target gene express ion. (C) 2000 Academic Press.