Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover.
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.
Di Guglielmo
Gianni M
GM
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
Le Roy
Christine
C
Goodfellow
Anne F
AF
Wrana
Jeffrey L
JL
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism* / Q000648:ultrastructure; D002451:Cell Compartmentation / Q000502:physiology*; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000378:metabolism / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000648:ultrastructure; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005057:Eukaryotic Cells / Q000378:metabolism / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008025:Ligases / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism / Q000648:ultrastructure; D008854:Microscopy, Electron; D021381:Protein Transport / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism* / Q000648:ultrastructure; D012697:Serine Endopeptidases; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism / Q000648:ultrastructure; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; C116420:ZFYVE16 protein, human; D012697:Serine Endopeptidases; D008025:Ligases