Ligand‐Independent Degradation of Epidermal Growth Factor Receptor Involves Receptor Ubiquitylation and Hgs, an Adaptor Whose Ubiquitin‐Interacting Motif Targets Ubiquitylation by Nedd4

• Published in: Traffic (Copenhagen, Denmark) Vol. 3; no. 10; pp. 740 - 751
• Main Authors: Katz, Menachem, Shtiegman, Keren, Tal‐Or, Pazit, Yakir, Liat, Mosesson, Yaron, Harari, Daniel, Machluf, Yossi, Asao, Hironobu, Jovin, Thomas, Sugamura, Kazuo, Yarden, Yosef
• Format: Journal Article
• Language: English
• Published: Oxford, UK Munksgaard International Publishers 01-10-2002
• Subjects: Amino Acid Motifs; Animals; CHO Cells; Cricetinae; Cytoplasm - metabolism; endocytosis; Endosomal Sorting Complexes Required for Transport; epidermal growth factor; Hgs; Hrs; Hydrolysis; Ligands; Nedd4; Phosphoproteins - metabolism; Receptor, Epidermal Growth Factor - metabolism; signal transduction; tyrosine kinase; ubiquitin; Ubiquitin - metabolism
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1034/j.1600-0854.2002.31006.x

Ligand‐dependent endocytosis of the epidermal growth factor receptor (EGFR) involves recruitment of a ubiquitin ligase, and sorting of ubiquitylated receptors to lysosomal degradation. By studying Hgs, a mammalian homolog of a yeast vacuolar‐sorting adaptor, we provide information on the less understood, ligand‐independent pathway of receptor endocytosis and degradation. Constitutive endocytosis involves receptor ubiquitylation and translocation to Hgs‐containing endosomes. Whereas the lipid‐binding motif of Hgs is necessary for receptor endocytosis, the ubiquitin‐interacting motif negatively regulates receptor degradation. We demonstrate that the ubiquitin‐interacting motif is endowed with two functions: it binds ubiquitylated proteins and it targets self‐ubiquitylation by recruiting Nedd4, an ubiquitin ligase previously implicated in endocytosis. Based upon the dual function of the ubiquitin‐interacting motif and its wide occurrence in endocytic adaptors, we propose a ubiquitin‐interacting motif network that relays ubiquitylated membrane receptors to lysosomal degradation through successive budding events.