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22 (17): 4465-4477

Copyright © 2003 by the European Molecular Biology Organization.

TLP, a novel modulator of TGF-ß signaling, has opposite effects on Smad2- and Smad3-dependent signaling

Angelina Felici, Jens U. Wurthner1, W.Tony Parks2, Louise Ruh-yu Giam, Michael Reiss3, Tatiana S. Karpova4, James G. McNally4, and Anita B. Roberts5

Laboratory of Cell Regulation and Carcinogenesis and 4 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055 and 3 Division of Medical Oncology, Department of Internal Medicine, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA 1 Present address: Institute for Medical Microbiology and Virology, University of Düsseldorf, Universitätsstraße 1-Bldg 22.21, 40225 Düsseldorf, Germany 2 Present address: Department of Pathology, HSB E506 Campus Box 357470, University of Washington, 1959 NE Pacific Avenue, Seattle, WA 98195, USA 5 Corresponding author e-mail: robertsa@dce41.nci.nih.govA.Felici and J.U.Wurthner contributed equally to this work

Abstract: Transforming growth factor-ß (TGF-ß) is a multifunctional cytokine signaling to the nucleus through cell surface transmembrane receptor serine/threonine kinases and cytoplasmic effectors, including Smad proteins. We describe a novel modulator of this pathway, TLP (TRAP-1-like protein), which is 25% identical to the previously described Smad4 chaperone, TRAP-1, and shows identical expression patterns in human tissues. Endogenous TLP associates with both active and kinase-deficient TGF-ß and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-ß/activin signaling. Overexpression of TLP represses the ability of TGF-ß to induce transcription from SBE-Luc, a Smad3/4-specific reporter, while it potentiates transcription from ARE-Luc, a Smad2/4-specific reporter. Consistent with this, TLP inhibits the formation of Smad3/4 complexes in the absence of effects on phosphorylation of Smad3, while it affects neither Smad2 phosphorylation nor hetero-oligomerization. We propose that TLP might regulate the balance of Smad2 and Smad3 signaling by localizing Smad4 intracellularly, thus contributing to cellular specificity of TGF-ß transcriptional responses in both normal and pathophysiology.

Key Words: Keywords: Smad proteins/TGF-ß signaling/TRAP-1/TGF-ß receptors

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