HEPATOCYTE GROWTH-FACTOR (HGF) RECEPTOR EXPRESSION IS INDUCIBLE AND IS PART OF THE DELAYED-EARLY RESPONSE TO HGF

The c-MET proto oncogene encodes the tyrosine kinase receptor for hepa tocyte growth factor (HGF), also known as scatter factor, a potent mit ogen and motogen for epithelial cells. The level of the HGF receptor e xpressed by epithelial cells varies in different growth conditions, be ing lower in growth arrested confluent monolayers and higher in growin g sparse cells. The amount of HGF receptor mRNA increases from 3- to 5 -fold after stimulation of confluent monolayers by serum and up to 10- fold after stimulation of protein kinase C by 12-O-tetradecanoylphorbo l-13-acetate (TPA). An increased level of the receptor mRNA was also o bserved after cell stimulation with nanomolar concentration of HGF its elf. The effect was transient, dose, and time dependent. Transcription of a reporter gene under control of the cloned 297 base pair c-MET pr omoter was also stimulated by serum, TPA, or HGF. The accumulation of specific mRNA is followed by appearance of the HGF receptor precursor protein, which is further processed to the receptor mature form. After HGF stimulation, HGF receptor expression follows c-FOS and c-JUN indu ction with a peak similar to 4 h. Pretreatment with the protein synthe sis inhibitor puromycin strongly reduced the response to HGF, while cy cloheximide alone increased the level of the receptor mRNA These data show that c-MET behaves as a delayed early-response gene and suggest t hat the HGF response is autoamplified by inducing the specific recepto r.