title: Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and Hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4.
abstract: 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.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Menachem
authors.initials: M
authors.lastname: Katz
authors.forename: Keren
authors.initials: K
authors.lastname: Shtiegman
authors.forename: Pazit
authors.initials: P
authors.lastname: Tal-Or
authors.forename: Liat
authors.initials: L
authors.lastname: Yakir
authors.forename: Yaron
authors.initials: Y
authors.lastname: Mosesson
authors.forename: Daniel
authors.initials: D
authors.lastname: Harari
authors.forename: Yossi
authors.initials: Y
authors.lastname: Machluf
authors.forename: Hironobu
authors.initials: H
authors.lastname: Asao
authors.forename: Thomas
authors.initials: T
authors.lastname: Jovin
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D066246:ErbB Receptors / Q000378:metabolism*; D006868:Hydrolysis; D008024:Ligands; D010750:Phosphoproteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D008024:Ligands; D010750:Phosphoproteins; D025801:Ubiquitin; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D066246:ErbB Receptors