Suppression of the ligand-mediated down-regulation of epidermal growth factor receptor by Ymer, a novel tyrosine-phosphorylated and ubiquitinated protein.
The ligand-mediated down-regulation of the growth factor receptors is preceded by the involvement of various other factors. In particular, a ubiquitin ligase, Cbl, plays a central role in this event. Several candidates that have potential effects on the negative control of the epidermal growth factor (EGF) receptor have now been identified by our recent studies in phospho-proteomics. Among these molecules, we focus on characterizing a novel protein, Ymer, which is a tyrosine-phosphorylated and ubiquitinated protein. Ymer is found to be phosphorylated at tyrosine 145 and 146 upon EGF stimulation, and lysine 129 of Ymer has been identified as a ubiquitination site. Ymer has two motifs interacting with the ubiquitin (MIU) domains that might function as a binding site for the ubiquitinated EGF receptor. Although Ymer and EGF receptors are associated in an EGF-dependent manner, their interaction is required not only for MIU domains but also for the tyrosine phosphorylation of Ymer. Phosphorylated Ymer is mainly located at the plasma membrane with EGF receptor and functions in its endocytosis and degradation. Furthermore, EGF-mediated secondary modifications of an activated-EGF receptor are inhibited by overexpressing Ymer in COS7 cells. Therefore, Ymer may have competitive effects on the activation of the EGF receptor. Our findings suggest that Ymer functions as a novel inhibitor for the down-regulation of the EGF receptor and plays a crucial role for regulating the amount of the EGF receptor on the cell surface membrane.
Tashiro
Kyoko
K
Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan and Harima Institute at Spring-8, RIKEN, Hyogo 679-5148, Japan.
Konishi
Hiroaki
H
Sano
Etsuko
E
Nabeshi
Hiromi
H
Yamauchi
Emiko
E
Taniguchi
Hisaaki
H
D002460:Cell Line; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine; D025801:Ubiquitin / Q000378:metabolism
C478972:CCDC50 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D011506:Proteins; D025801:Ubiquitin; D014443:Tyrosine; D066246:ErbB Receptors