Monoubiquitinylation regulates endosomal localization of Lst2, a negative regulator of EGF receptor signaling.
Genetic screens performed in worms identified major regulators of the epidermal growth factor receptor (EGFR) pathway, including the ubiquitin ligase Cbl/SLI-1. Here we focus on the less-characterized Lst2 protein and confirm suppression of MAPK signals. Unexpectedly, human Lst2, a monoubiquitinylated phosphoprotein, does not localize to endosomes, despite an intrinsic phosphoinositol-binding ... FYVE domain. By constructing an ubiquitinylation-defective mutant and an ubiquitin fusion, we conclude that endosomal localization of Lst2, along with an ability to divert incoming EGFR molecules to degradation in lysosomes, is regulated by ubiquitinylation/deubiquitinylation cycles. Consistent with bifurcating roles, Lst2 physically binds Trim3/BERP, which interacts with Hrs and a complex that biases cargo recycling. These results establish an ubiquitin-based endosomal switch of receptor sorting, functionally equivalent to the mechanism inactivating Hrs via monoubiquitinylation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Carrier Proteins, Endocytosis, Endosomal Sorting Complexes Required for Transport, Endosomes, Hela Cells, Humans, Lysine, Membrane Proteins, Phosphoproteins, Phosphorylation, Protein Structure, Tertiary, Receptor, Epidermal Growth Factor, Signal Transduction, Ubiquitination, Zinc Fingers
Adaptor Proteins, Signal Transducing, Carrier Proteins, Endocytosis, Endosomal Sorting Complexes Required for Transport, Endosomes, Hela Cells, Humans, Lysine, Membrane Proteins, Phosphoproteins, Phosphorylation, Protein Structure, Tertiary, Receptor, Epidermal Growth Factor, Signal Transduction, Ubiquitination, Zinc Fingers
Dev. Cell
Date: May. 01, 2009
PubMed ID: 19460345
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