Intron-exon structure of the MET gene and cloning of an alternatively-spliced Met isoform reveals frequent exon-skipping of a single large internal exon

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional factor that stimulates epithelial cell mitogenesis, motility, invasion, and morphogenesis. Its receptor is encoded by the MET proto-oncogene, a transmembrane receptor tyrosine kinase. Several studies have suggested a role for MET as a dominant oncogene in tumor development and progression. Conversely, MET is located at a region on chromosome 7q31 frequently deleted in carcinomas, suggesting that recessive mutations in MET may exist in certain cancers. To facilitate a search for mutations in MET, we have obtained the intron-exon structure of the human MET gene. We present the genomic structure of the first member of the Met receptor family to be characterized. Interestingly, MET contains a large second exon of 1214 nucleotides. We show that this exon, containing the AUG for the Met receptor, is frequently skipped in normal human tissues and cell lines, and corresponds to a ubiquitously expressed 7 kb Met transcript. This transcript yields no detectable protein product in vivo. Thus, unlike other genes, in which alternative splicing often gives rise to proteins with distinct activities, exon-skipping of MET exon 2 is predicted to decrease the abundance of a Met mRNA encoding a functional Met receptor.