Isoforms of the met receptor tyrosine kinase.

Hepatocyte growth factor/scatter factor (HGF-SF), a multifunctional cytokine, is the ligand for the met receptor tyrosine kinase. Multiple met mRNAs of 8, 7, 5, 3 and 1.6-kb in size have been identified in human cell lines and tissue. To investigate the biological function of these various isoforms we have isolated cDNA clones corresponding to some of the differentially spliced met mRNAs. Characterization of these cDNAs suggests that by alternative splicing and possibly by use of distinct transcription initiation sites the met HGF-SF receptor is expressed in various isoforms. We have demonstrated that there are two met 8-kb mRNAs that differ through alternative splicing of a 54-bp exon that maintains the open reading frame such that these proteins differ by only 18 aa in their extracellular domain. The -54-bp form corresponds to the most abundant 8-kb met RNA and encodes the p190 met alpha beta heterodimer. In contrast the +54-bp mRNA encodes a protein of 170 kd that is not cleaved yet is expressed at the cell surface and has in vitro kinase activity. The 7-kb mRNA differs by alternative splicing such that it encodes a protein with a distinct amino terminus. Unlike these met RNAs, the 1.6-kb mRNA has new 5' and 3' sequences and encodes a protein that shares homology with the extracellular domain of the met RTK but has a unique carboxy terminus. Thus multiple met RNAs encode proteins that differ in both the extracellular ligand binding domain and within the cytoplasmic domain suggesting that these different met isoforms may have distinct biological activities.