Abstract
Endocytosis of cell surface receptors is an important regulatory event in signal transduction. The transforming growth factor beta (TGF-beta) 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-beta 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-beta 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-beta receptors into distinct endocytic compartments regulates Smad activation and receptor turnover.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Carrier Proteins / metabolism
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Caveolae / metabolism*
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Caveolae / ultrastructure
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Cell Compartmentation / physiology*
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Cells, Cultured
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Clathrin-Coated Vesicles / metabolism
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Clathrin-Coated Vesicles / ultrastructure
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / ultrastructure
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Endocytosis / physiology*
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Endosomes / metabolism
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Endosomes / ultrastructure
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Eukaryotic Cells / metabolism
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Eukaryotic Cells / ultrastructure
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Fluorescent Antibody Technique
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Humans
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Intracellular Signaling Peptides and Proteins*
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Ligases / metabolism
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Membrane Microdomains / metabolism*
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Membrane Microdomains / ultrastructure
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Membrane Proteins / metabolism
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Membrane Proteins / ultrastructure
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Microscopy, Electron
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Protein Transport / physiology*
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Receptors, Transforming Growth Factor beta / metabolism*
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Receptors, Transforming Growth Factor beta / ultrastructure
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Serine Endopeptidases*
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Signal Transduction / physiology*
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Smad2 Protein
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Smad7 Protein
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Trans-Activators / metabolism
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Trans-Activators / ultrastructure
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Ubiquitin-Protein Ligases
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Vesicular Transport Proteins
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, Transforming Growth Factor beta
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SMAD2 protein, human
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SMAD7 protein, human
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Smad2 Protein
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Smad7 Protein
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Trans-Activators
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Vesicular Transport Proteins
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early endosome antigen 1
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SMURF2 protein, human
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Ubiquitin-Protein Ligases
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ZFYVE16 protein, human
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Serine Endopeptidases
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Ligases