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Carcinogenesis Advance Access originally published online on March 26, 2009
Carcinogenesis 2009 30(8):1281-1287; doi:10.1093/carcin/bgp071
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The type III transforming growth factor-β receptor negatively regulates nuclear factor kappa B signaling through its interaction with β-arrestin2

Hye Jin You1, Tam How2 and Gerard C. Blobe2,3,*

1 Division of Basic and Applied Sciences, Carcinogenesis Branch, National Cancer Center, Jungbalsan-ro 111, Ilsandong-gu, Goyang, Gyeonggi 410-769, South Korea
2 Department of Medicine
3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham NC 27708, USA

* To whom correspondence should be addressed. Tel: +1 919 668 1352; Fax: +1 919 681 6906; Email: blobe001{at}mc.duke.edu

Transforming growth factor-β (TGF-β) increases or decreases nuclear factor kappa B (NF{kappa}B) signaling in a context-dependent manner through mechanisms that remain to be defined. The type III transforming growth factor-β receptor (TβRIII) is a TGF-β superfamily co-receptor with emerging roles in both mediating and regulating TGF-β superfamily signaling. We have previously reported a novel interaction of TβRIII with the scaffolding protein, β-arrestin2, which results in TβRIII internalization and downregulation of TGF-β signaling. β-arrestin2 also scaffolds interacting receptors with the mitogen-activated protein kinase and NF{kappa}B-signaling pathways. Here, we demonstrate that TβRIII, through its interaction with β-arrestin2, negatively regulates NF{kappa}B signaling in MCF10A breast epithelial and MDA-MB-231 breast cancer cells. Increasing TβRIII expression reduced NF{kappa}B-mediated transcriptional activation and I{kappa}B{alpha} degradation, whereas a TβRIII mutant unable to interact with β-arrestin2, TβRIII-T841A, had no effect. In a reciprocal manner, short hairpin RNA-mediated silencing of either TβRIII expression or β-arrestin2 expression increased NF{kappa}B-mediated transcriptional activation and I{kappa}B{alpha} degradation. Functionally, TβRIII-mediated repression of NF{kappa}B signaling is important for TβRIII-mediated inhibition of breast cancer cell migration. These studies define a mechanism through which TβRIII regulates NF{kappa}B signaling and expand the roles of this TGF-β superfamily co-receptor in regulating epithelial cell homeostasis.

Abbreviations: GPCR, G-protein-coupled receptor; IKK, I{kappa}B kinase; shRNA, short hairpin RNA; siRNA, small interfering RNA; TGF-β, transforming growth factor-β; TβRIII, type III transforming growth factor-β receptor

Received January 26, 2009; revised March 12, 2009; accepted March 18, 2009.


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