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MBC in Press, published online ahead of print August 24, 2005
Mol. Biol. Cell 10.1091/mbc.E05-06-0560

A more recent version of this article appeared on November 1, 2005
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Submitted on June 24, 2005
Revised on August 1, 2005
Accepted on August 12, 2005

Regulation of EGF Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Emi Mizuno,* Takanobu Iura,* Akiko Mukai,* Tamotsu Yoshimori,{dagger} Naomi Kitamura,* and Masayuki Komada*

*Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan; {dagger}Department of Cell Genetics, National Institute of Genetics, Mishima 411-8540, Japan

Monitoring Editor: Suzanne Pfeffer

Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of EGF receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically-inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.

Address correspondence to: Masayuki Komada (makomada{at}bio.titech.ac.jp)




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