Disruption of Transforming Growth Factor β Signaling by a Novel Ligand-dependent Mechanism
| Autor: | Alexander L. Kovalchuk, Michael Potter, Tania Fernandez, Valery Bliskovski, Stephanie R. Amoroso, Shellyann Sharpe, Gary M. Jones, Lalage M. Wakefield, John J. Letterio, Seong-Jin Kim |
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| Rok vydání: | 2002 |
| Předmět: |
signal-transduction
receptor Blotting Western Immunology Smad2 Protein Protein Serine-Threonine Kinases Ligands Article Mice Paracrine signalling plasmacytoma trafficking Transforming Growth Factor beta Animals Immunology and Allergy RNA Antisense Autocrine signalling R-SMAD biology Terpenes Cell growth Cell Membrane Receptor Transforming Growth Factor-beta Type II Transforming growth factor beta intracellular Cell biology DNA-Binding Proteins Autocrine Communication Protein Transport Trans-Activators biology.protein Signal transduction Receptors Transforming Growth Factor beta Intracellular Protein Binding Signal Transduction Transforming growth factor |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20011521 |
| Popis: | Transforming growth factor (TGF)-beta is the prototype in a family of secreted proteins that act in autocrine and paracrine pathways to regulate cell development and function. Normal cells typically coexpress TGF-beta receptors and one or more isoforms of TGF-beta, thus the synthesis and secretion of TGF-beta as an inactive latent complex is considered an essential step in regula-ting the activity of this pathway. To determine whether intracellular activation of TGF-beta results in TGF-beta ligand-receptor interactions within the cell, we studied pristane-induced plasma cell tumors (PCTs). We now demonstrate that active TGF-beta1 in the PCT binds to intracellular TGF-beta type II receptor (TbetaRII). Disruption of the expression of TGF-beta1 by antisense TGF-beta1 mRNA restores localization of TbetaRII at the PCT cell surface, indicating a ligand-induced impediment in receptor trafficking. We also show that retroviral expression of a truncated, dominant-negative TbetaRII (dnTbetaRII) effectively competes for intracellular binding of active ligand in the PCT and restores cell surface expression of the endogenous TbetaRII. Analysis of TGF-beta receptor-activated Smad2 suggests the intracellular ligand-receptor complex is not capable of signaling. These data are the first to demonstrate the formation of an intracellular TGF-beta-receptor complex, and define a novel mechanism for modulating the TGF-beta signaling pathway. |
| Databáze: | OpenAIRE |
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