Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3.
The epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases plays fundamental roles in the regulation of cell survival, proliferation, and differentiation. Here, we present evidence that ErbB3 is degraded by proteasomes, and that Nrdp1 (referred to as FLRF in mice) associates with ErbB3 and stimulates its ubiquitination and degradation by proteasomes. Nrdp1 mRNAs are expressed in a variety of human tissues. The N-terminal half of Nrdp1 possesses an atypical RING finger domain, which is required for enhancing ErbB3 degradation. Its C-terminal half by itself associates with ErbB3 and raises ErbB3 levels in cells, probably by acting as a dominant-negative form of Nrdp1. In cell-free systems, Nrdp1 has ubiquitin ligase (E3) activity and ubiquitinates ErbB3, as well as itself, in the presence of the ubiquitin-carrier protein (E2), UbcH5. These data indicate that Nrdp1 is a RING finger-type of ubiquitin ligase, which promotes degradation of ErbB3 by proteasomes and, thus, may be an important factor influencing cell growth.
Qiu
Xiao-Bo
XB
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Goldberg
Alfred L
AL
D000595:Amino Acid Sequence; D002460:Cell Line; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010453:Peptide Synthases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D011506:Proteins; D025801:Ubiquitin; C117617:UBR5 protein, human; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D010453:Peptide Synthases