BCA, HGF, and proteasomes.

This is my reminiscent essay of my research life, but not a review article of specific subject. We found in the 1960s that BCAs (the branched chain amino acids, valine, leucine, and isoleucine) are unique in being the least metabolized amino acids in liver due to low activity of their transaminase. Later it was found clinically that BCAs are quite effective for recovery from hepatic encephalopathy. Furthermore, they could restore protein metabolism by stimulating synthesis and inhibiting degradation of body proteins under stress conditions. The signal of BCAs seems to be mediated by the amino acid sensor, Ssyl, which induces the amino acid permease AGP1. After liver injury, hepatocytes regenerate actively. In the 1980s, to study the molecular mechanism involved, we used primary cultured rat hepatocytes, the gene expressions of which respond very well to nutrients and hormones in the medium and to cell density. We identified HGF (hepatocyte growth factor) as a potent mitogen. The HGF receptor is cMet, an oncogene, and it initiates tyrosine phosphorylation in cellular signal transduction. The proteasome is a unique protease consisting of a very large multisubunit complex, which shows energy- and ubiquitin-dependent activity. In the 1990s we characterized the molecular structures of its subunits. Recently, proteasomes were found to degrade the HGF receptor, cMet. Furthermore, the Grrlp transcription factor, which is stimulated by Ssyl described above, has been identified as a ubiquitin-protein ligase. These studies on BCA, HGF, and proteasomes seemed to be unrelated to each other when I was working, but recent studies have shown that they are very closely related. So I would like to discuss the relations of my old work to recent findings.