Distinct endocytic pathways regulate TGF-β receptor signalling and turnover

GM Di Guglielmo, C Le Roy, AF Goodfellow… - Nature cell …, 2003 - nature.com
GM Di Guglielmo, C Le Roy, AF Goodfellow, JL Wrana
Nature cell biology, 2003nature.com
Endocytosis of cell surface receptors is an important regulatory event in signal transduction.
The transforming growth factor β (TGF-β) superfamily signals to the Smad pathway through
heteromeric Ser-Thr kinase receptors that are rapidly internalized and then downregulated
in a ubiquitin-dependent manner. Here we demonstrate that TGF-β receptors internalize into
both caveolin-and EEA1-positive vesicles and reside in both lipid raft and non-raft
membrane domains. Clathrin-dependent internalization into the EEA1-positive endosome …
Abstract
Endocytosis of cell surface receptors is an important regulatory event in signal transduction. The transforming growth factor β (TGF-β) superfamily signals to the Smad pathway through heteromeric Ser-Thr kinase receptors that are rapidly internalized and then downregulated in a ubiquitin-dependent manner. Here we demonstrate that TGF-β receptors internalize into both caveolin- and EEA1-positive vesicles and reside in both lipid raft and non-raft membrane domains. Clathrin-dependent internalization into the EEA1-positive endosome, where the Smad2 anchor SARA is enriched, promotes TGF-β signalling. In contrast, the lipid raft-caveolar internalization pathway contains the Smad7-Smurf2 bound receptor and is required for rapid receptor turnover. Thus, segregation of TGF-β receptors into distinct endocytic compartments regulates Smad activation and receptor turnover.
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