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Vol. 17, Issue 6, 2513-2523, June 2006
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*Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway; and Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada M5G 1X8
Submitted October 4, 2005;
Revised March 6, 2006;
Accepted March 9, 2006
Monitoring Editor: Sandra Schmid
The endosomal sorting complexes required for transport, ESCRT-I, -II, and -III, are thought to mediate the biogenesis of multivesicular endosomes (MVEs) and endosomal sorting of ubiquitinated membrane proteins. Here, we have compared the importance of the ESCRT-I subunit tumor susceptibility gene 101 (Tsg101) and the ESCRT-III subunit hVps24/CHMP3 for endosomal functions and receptor signaling. Like Tsg101, endogenous hVps24 localized mainly to late endosomes. Depletion of hVps24 by siRNA showed that this ESCRT subunit, like Tsg101, is important for degradation of the epidermal growth factor (EGF) receptor (EGFR) and for transport of the receptor from early endosomes to lysosomes. Surprisingly, however, whereas depletion of Tsg101 caused sustained EGF activation of the mitogen-activated protein kinase pathway, depletion of hVps24 had no such effect. Moreover, depletion of Tsg101 but not of hVps24 caused a major fraction of internalized EGF to accumulate in nonacidified endosomes. Electron microscopy of hVps24-depleted cells showed an accumulation of EGFRs in MVEs that were significantly smaller than those in control cells, probably because of an impaired fusion with lyso-bisphosphatidic acid-positive late endosomes/lysosomes. Together, our results reveal functional differences between ESCRT-I and ESCRT-III in degradative protein trafficking and indicate that degradation of the EGFR is not required for termination of its signaling.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Harald Stenmark ( stenmark{at}ulrik.uio.no)
Abbreviations used: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ESCRT, endosomal sorting complex required for transport; Hrs, hepatocyte growth factor-regulated tyrosine kinase substrate; MVE, multivesicular endosome; PI3P, phosphatidylinositol 3-phosphate; siRNA, small-interfering RNA; Tsg101, tumor susceptibility gene 101; vps, vacuolar protein sorting
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