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Carcinogenesis Advance Access published online on September 3, 2007
Carcinogenesis, doi:10.1093/carcin/bgm195
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The type III TGF-ß Receptor Signals through both Smad3 and the p38 MAP Kinase Pathways to Contribute to Inhibition of Cell Proliferation

Hye Jin You*, Monique W. Bruinsma*, Tam How*, Julie H. Ostrander* and Gerard C. Blobe*,{dagger},{ddagger}

* Duke University Medical Center, Departments of Medicine
{dagger} Pharmacology and Cancer Biology, Durham, NC 27710

{ddagger} Corresponding author: Gerard C. Blobe 221B MSRB Research Drive, Box 2631 DUMC, Durham, NC 27710, Tel: (919) 668-1352; Fax: (919) 668-2458; Email: blobe001{at}mc.duke.edu

Transforming growth factor ß (TGFß) has an important role as a negative regulator of cellular proliferation. The type III TGFß receptor (TßRIII) has an emerging role as both a TGFß superfamily co-receptor and in mediating signaling through its cytoplasmic domain. In L6 myoblasts, TßRIII expression enhanced TGFß1-mediated growth inhibition, with this effect mediated, in part, by the TßRIII cytoplasmic domain. The effects of TßRIII were not due to altered ligand presentation or to differences in Smad2 phosphorylation. Instead, TßRIII specifically increased Smad3 phosphorylation, both basal and TGFß-stimulated Smad3 nuclear localization and Smad3-dependent activation of reporter genes independent of its cytoplasmic domain. Conversely, SB431542, a type I TGFß receptor (TßRI) inhibitor, as well as dominant negative Smad3 specifically and significantly abrogated the effects of TßRIII on TGFß1-mediated inhibition of proliferation. TßRIII also specifically increased p38 phosphorylation, and SB203580, a p38 kinase inhibitor, specifically and significantly abrogated the effects of TßRIII/TGFß1-mediated inhibition of proliferation in L6 myoblasts and in primary human epithelial cells. Importantly, treatment with the TßRI and p38 inhibitors together had additive effects on abrogating TßRIII/TGFß1-mediated inhibition of proliferation. In a reciprocal manner, shRNA-mediated knockdown of endogenous TßRIII in various human epithelial cells attenuated TGFß1-mediated inhibition of proliferation. Taken together these data demonstrate that TßRIII contributes to and enhances TGFß-mediated growth inhibition through both TßRI/Smad3-dependent and p38 MAP kinase pathways.

Key Words: TGFß signaling • co-receptors • MAP kinase • growth regulation

Received July 3, 2007; revised August 15, 2007; accepted August 17, 2007.


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