title: Disruption of transforming growth factor beta signaling by a novel ligand-dependent mechanism.
abstract: 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.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, The National Cancer Institute, The National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Fernandez
authors.forename: Stephanie
authors.initials: S
authors.lastname: Amoroso
authors.forename: Shellyann
authors.initials: S
authors.lastname: Sharpe
authors.forename: Gary M
authors.initials: GM
authors.lastname: Jones
authors.forename: Valery
authors.initials: V
authors.lastname: Bliskovski
authors.forename: Alexander
authors.initials: A
authors.lastname: Kovalchuk
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Potter
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D010954:Plasmacytoma / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D016372:RNA, Antisense / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein; D013729:Terpenes / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D016372:RNA, Antisense; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D013729:Terpenes; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C009042:pristane; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II