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¹ Department of Biochemistry, University of Geneva, 1211-Geneva-4, Switzerland
² Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway

Address correspondence to J. Gruenberg, Department of Biochemistry, University of Geneva, 30 quai E Ansermet, 1211-Geneva-4, Switzerland. Tel.: 41-22-379-6464. Fax: 41-22-379-6464. email: jean.gruenberg{at}biochem.unige.ch

While evidence is accumulating that phosphoinositide signaling plays a crucial role in growth factor and hormone receptor down-regulation, this signaling pathway has also been proposed to regulate endosomal membrane transport and multivesicular endosome biogenesis. Here, we have followed the fate of the down-regulated EGF receptor (EGFR) and bulk transport (fluid phase) markers in the endosomal pathway in vivo and in vitro. We find that bulk transport from early to late endosomes is not affected after inhibition of the phosphatidylinositol-3-phosphate (PI3P) signaling pathway, but that the EGFR then remains trapped in early endosomes. Similarly, we find that hepatocyte growth factor–regulated tyrosine kinase substrate (Hrs) is not directly involved in bulk solute transport, but is required for EGFR sorting. These observations thus show that transport and sorting can be uncoupled in the endosomal pathway. They also show that PI3P signaling does not regulate the core machinery of endosome biogenesis and transport, but controls the sorting of down-regulated receptor molecules in early endosomes via Hrs.

Key Words: EGF receptor; phosphoinositide; FYVE; PHOX and PX; multivesicular body

Abbreviations used in this paper: bHRP, biotinylated HRP; ECV, endosomal carrier vesicle; EEA1, early endosomal antigen 1; EGFR, EGF receptor; Hrs, hepatocyte growth factor–regulated tyrosine kinase substrate; LBPA, lysobisphosphatidic acid; PI3P, phosphatidylinositol-3-phosphate; TfR, transferrin receptor.

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