The Journal of Experimental Medicine
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Published online 13 May 2002 doi:10.1084/jem.20011521
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© Rockefeller University Press, 0022-1007/2002/5/1247/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 10, May 20, 2002 1247-1255

Disruption of Transforming Growth Factor ß Signaling by a Novel Ligand-dependent Mechanism

Tania Fernandez1, Stephanie Amoroso1, Shellyann Sharpe1, Gary M. Jones2, Valery Bliskovski2, Alexander Kovalchuk2, Lalage M. Wakefield1, Seong-Jin Kim1, Michael Potter2 and John J. Letterio1

1 Laboratory of Cell Regulation and Carcinogenesis, The National Cancer Institute, The National Institutes of Health, Bethesda, MD 20892
2 The Laboratory of Genetics, The National Cancer Institute, The National Institutes of Health, Bethesda, MD 20892

Address correspondence to John J. Letterio, Lab of Cell Regulation and Carcinogenesis, Building 41, Room C629, 41 Library Drive, Bethesda, MD 20892. Phone: 301-496-8348; Fax: 303-496-8395; E-mail: letterij{at}mail.nih.gov

Transforming growth factor (TGF)-ß 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-ß receptors and one or more isoforms of TGF-ß, thus the synthesis and secretion of TGF-ß 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-ß results in TGF-ß ligand–receptor interactions within the cell, we studied pristane-induced plasma cell tumors (PCTs). We now demonstrate that active TGF-ß1 in the PCT binds to intracellular TGF-ß type II receptor (TßRII). Disruption of the expression of TGF-ß1 by antisense TGF-ß1 mRNA restores localization of TßRII at the PCT cell surface, indicating a ligand-induced impediment in receptor trafficking. We also show that retroviral expression of a truncated, dominant-negative TßRII (dnTßRII) effectively competes for intracellular binding of active ligand in the PCT and restores cell surface expression of the endogenous TßRII. Analysis of TGF-ß 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-ß–receptor complex, and define a novel mechanism for modulating the TGF-ß signaling pathway.

Key Words: receptor • trafficking • intracellular • signal-transduction • plasmacytoma


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