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Vol. 14, Issue 9, 3675-3689, September 2003
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Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
Submitted December 13, 2002;
Revised April 24, 2003;
Accepted April 25, 2003
Monitoring Editor: Howard Riezman
Conjugation with ubiquitin acts as a sorting signal for proteins in the endocytic and biosynthetic pathways at the endosome. Signal-transducing adaptor molecule (STAM) proteins, STAM1 and STAM2, are associated with hepatocyte growth factor-regulated substrate (Hrs) but their function remains unknown. Herein, we show that STAM proteins bind ubiquitin and ubiquitinated proteins and that the tandemly located VHS (Vps27/Hrs/STAM) domain and ubiquitin-interacting motif serve as the binding site(s). STAM proteins colocalize with Hrs on the early endosome. Overexpression of STAM proteins, but not their mutants lacking the ubiquitin-binding activity, causes the accumulation of ubiquitinated proteins and ligand-activated epidermal growth factor receptor on the early endosome. These results suggest that through interaction with ubiquitinated cargo proteins on the early endosome via the VHS domain and ubiquitin-interacting motif, STAM proteins participate in the sorting of cargo proteins for trafficking to the lysosome.
Abbreviations used: ACLL, acidic-cluster dileucine; EGF, epidermal growth factor; ESCRT, endosomal sorting complex required for transport; GGA, Golgi-localizing/
-adaptin ear homology domain/ADP-ribosylation factor-binding; GST, glutathione S-transferase; Hrs, hepatocyte growth factor-regulated substrate; MVB, multivesicular body; SH3, Src homology 3; STAM, signal-transducing adaptor molecule; TGN, trans-Golgi network; UIM, ubiquitin-interacting motif; VHS, Vps27/Hrs/STAM; Vps, vacuolar protein sorting.
* Corresponding author. E-mail address: makomada{at}bio.titech.ac.jp.
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