Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and Hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4.
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.
Katz
Menachem
M
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Shtiegman
Keren
K
Tal-Or
Pazit
P
Yakir
Liat
L
Mosesson
Yaron
Y
Harari
Daniel
D
Machluf
Yossi
Y
Asao
Hironobu
H
Jovin
Thomas
T
Sugamura
Kazuo
K
Yarden
Yosef
Y
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*
D056827:Endosomal Sorting Complexes Required for Transport; D008024:Ligands; D010750:Phosphoproteins; D025801:Ubiquitin; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D066246:ErbB Receptors