Abstract
The c-MET proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), also known as scatter factor, a potent mitogen and motogen for epithelial cells. The level of the HGF receptor expressed by epithelial cells varies in different growth conditions, being lower in growth arrested confluent monolayers and higher in growing 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-tetradecanoylphorbol-13-acetate (TPA). An increased level of the receptor mRNA was also observed after cell stimulation with nanomolar concentration of HGF itself. The effect was transient, dose, and time-dependent. Transcription of a reporter gene under control of the cloned 297 base pair c-MET promoter 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 induction with a peak approximately 4 h. Pretreatment with the protein synthesis inhibitor puromycin strongly reduced the response to HGF, while cycloheximide alone increased the level of the receptor mRNA. These data show that c-MET behaves as a delayed early-response gene and suggest that the HGF response is autoamplified by inducing the specific receptor.
Highlights
Pressed by epithelialcellsvariesindifferentgrowth is secreted asa biologically inactive single chain precurs(oprroconditions, being lower in growth arrested confluent
Activation takes monolayersandhigheringrowingsparsecells.The place by proteolytic cleavage in the extracellular environment, amountof HGF receptor mRNA increases from 3- to and it is mediated by specific HGF convertases, including the &fold after stimulation of confluent monolayers by se- urokinase-type plasminogen activatoreand a novel serineprotease homologous to the blood
HGF Receptor mRNA Accumulates in Response toCell Stimulation by Serum or TPA-The effect of serum stimulation on the level of mRNAencoding the HGFreceptor was measured in A549 cells by Northern blot analysis
Summary
12-0-tetradecanoylphorbol-13-acetateE;GF,epidermalgrowth factor; PDGF, platelet-derivedgrowth factor; PIPES, 1,4-piperazineethansulfonic acid; SSC,saline sodium citrate; uPA, urokinase-typeplasminogen tor is detectable in cells of epithelial origin, mainly localized in theproliferative compartments Prat et al.,1991a), in endotheliaclells (Bussolino et al, 19921, HGF Receptor Expression in melanocytes (Natali et al, 19931, and inmicroglial cells (Di Renzo et al, 1993). In thiswork we show that expression of the HGFreceptor is inducible at transcriptional level. The receptor expression varies according to the growing conditions of the cells and following stimulation with serum or phorbol esters. HGF itself up-regulates the mRNA levels of its own receptor and induces expressionof uPA, a n enzyme playinga key role in the activation of pro-HGF
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