Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:BCA, HGF, and proteasomes. 1060 2

The activation and phosphorylation of Met, the receptor tyrosine kinase (RTK) for hepatocyte growth factor, initiates the recruitment of multiple signaling proteins, one of which is c-Cbl, a ubiquitin-protein ligase. c-Cbl promotes ubiquitination and enhances the down-modulation of the Met receptor and other RTKs, targeting them for lysosomal sorting and subsequent degradation. The ubiquitination of Met by c-Cbl requires the direct interaction of the c-Cbl tyrosine kinase binding (TKB) domain with tyrosine 1003 in the Met juxtamembrane domain. Although a consensus for c-Cbl TKB domain binding has been established ((D/N)XpYXX(D/E0phi), this motif is not present in Met, suggesting that other c-Cbl TKB domain binding motifs may exist. By alanine-scanning mutagenesis, we have identified a DpYR motif including Tyr(1003) as being important for the direct recruitment of the c-Cbl TKB domain and for ubiquitination of the Met receptor. The substitution of Tyr(1003) with phenylalanine or substitution of either aspartate or arginine residues with alanine impairs c-Cbl-recruitment and ubiquitination of Met and results in the oncogenic activation of the Met receptor. We demonstrate that the TKB domain of Cbl-b, but not Cbl-3, binds to the Met receptor and requires an intact DpYR motif. Modeling studies suggest the presence of a salt bridge between the aspartate and arginine residues that would position pTyr(1003) for binding to the c-Cbl TKB domain. The DpYR motif is conserved in other members of the Met RTK family but is not present in previously identified c-Cbl-binding proteins, identifying DpYR as a new binding motif for c-Cbl and Cbl-b.
 ...
PMID:A conserved DpYR motif in the juxtamembrane domain of the Met receptor family forms an atypical c-Cbl/Cbl-b tyrosine kinase binding domain binding site required for suppression of oncogenic activation. 1512 9

The small GTPase Rac1 is a key regulator of cell motility. Multiple mechanisms regulate Rac1 activity including its ubiquitylation and subsequent degradation. Here, we identify the tumour suppressor HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) as an E3 ubiquitin ligase responsible for Rac1 degradation following activation by a migration stimulus. We show that HACE1 and Rac1 interaction is enhanced by hepatocyte growth factor (HGF) signalling, a Rac activator and potent stimulus of cell migration. Furthermore, HACE1 catalyses the poly-ubiquitylation of Rac1 at lysine 147 following its activation by HGF, resulting in its proteasomal degradation. This negative feedback mechanism likely restricts cell motility. Consistent with this, HACE1 depletion is accompanied by increased total Rac1 levels and accumulation of Rac1 in membrane ruffles. Moreover, HACE1-depletion enhances cell migration independently of growth factor stimulation, which may have significance for malignant conversion. A non-ubiquitylatable Rac1 rescues the migration defect of Rac1-null cells to a greater extent than wild-type Rac1. These findings identify HACE1 as an antagonist of cell migration through its ability to degrade active Rac1.
 ...
PMID:The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation. 2261 15