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Our time-course experiment showed that EGFR undergoes polyubiquitination, which seemed to be facilitated during the transport to Hrs-positive endosomes. Use of a conjugation-defective ubiquitin mutant suggested that receptor polyubiquitination is required for efficient interaction with Hrs and subsequent sorting to lysosomes. Abrupt inhibition of the EGFR kinase activity resulted in dissociation of c-Cbl from EGFR. Concomitantly, EGFR was rapidly deubiquitinated and its degradation was delayed. We propose that sustained tyrosine phosphorylation of EGFR facilitates its polyubiquitination in endosomes and counteracts rapid deubiquitination, thereby ensuring Hrs-dependent lysosomal sorting.<\/jats:p>","DOI":"10.1091\/mbc.e07-10-0988","type":"journal-article","created":{"date-parts":[[2008,5,28]],"date-time":"2008-05-28T20:53:40Z","timestamp":1212008020000},"page":"3454-3462","source":"Crossref","is-referenced-by-count":97,"title":["Ubc4\/5 and c-Cbl Continue to Ubiquitinate EGF Receptor after Internalization to Facilitate Polyubiquitination and Degradation"],"prefix":"10.1091","volume":"19","author":[{"given":"Kyohei","family":"Umebayashi","sequence":"first","affiliation":[{"name":"*Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Stenmark","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biomedicine, University of Oslo and Department of Biochemistry, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamotsu","family":"Yoshimori","sequence":"additional","affiliation":[{"name":"*Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;"},{"name":"CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1076","reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"23083","DOI":"10.1074\/jbc.M513803200","volume":"281","author":"Agromayor M.","year":"2006","journal-title":"J. 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