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      Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover.

      Nature cell biology

      Carrier Proteins, metabolism, Caveolae, ultrastructure, Cell Compartmentation, physiology, Cells, Cultured, Clathrin-Coated Vesicles, DNA-Binding Proteins, Endocytosis, Endosomes, Eukaryotic Cells, Fluorescent Antibody Technique, Humans, Intracellular Signaling Peptides and Proteins, Vesicular Transport Proteins, Ligases, Membrane Microdomains, Membrane Proteins, Microscopy, Electron, Protein Transport, Receptors, Transforming Growth Factor beta, Serine Endopeptidases, Signal Transduction, Smad2 Protein, Smad7 Protein, Trans-Activators, Ubiquitin-Protein Ligases, Animals

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          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.

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          Most cited references 43

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          Lipid rafts and signal transduction.

           D Toomre,  K Simons (2000)
          Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.
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            TGF-beta signal transduction.

             J Massagué (1997)
            The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.
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              Mechanism of activation of the TGF-beta receptor.

              Transforming growth factor-beta (TGF-beta) signals by contacting two distantly related transmembrane serine/threonine kinases called receptors I and II. The role of these molecules in signalling has now been determined. TGF-beta binds directly to receptor II, which is a constitutively active kinase. Bound TGF-beta is then recognized by receptor I which is recruited into the complex and becomes phosphorylated by receptor II. Phosphorylation allows receptor I to propagate the signal to downstream substrates. This provides a mechanism by which a cytokine can generate the first step of a signalling cascade.
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                Author and article information

                Journal
                12717440
                10.1038/ncb975

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