Journal Article

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

Hye Jin You, Tam How and Gerard C. Blobe

in Carcinogenesis

Volume 30, issue 8, pages 1281-1287
Published in print August 2009 | ISSN: 0143-3334
Published online March 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp071
The type III transforming growth factor-β receptor negatively regulates nuclear factor kappa B signaling through its interaction with β-arrestin2

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Transforming growth factor-β (TGF-β) increases or decreases nuclear factor kappa B (NFκB) 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 NFκB-signaling pathways. Here, we demonstrate that TβRIII, through its interaction with β-arrestin2, negatively regulates NFκB signaling in MCF10A breast epithelial and MDA-MB-231 breast cancer cells. Increasing TβRIII expression reduced NFκB-mediated transcriptional activation and IκBα 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 NFκB-mediated transcriptional activation and IκBα degradation. Functionally, TβRIII-mediated repression of NFκB signaling is important for TβRIII-mediated inhibition of breast cancer cell migration. These studies define a mechanism through which TβRIII regulates NFκB signaling and expand the roles of this TGF-β superfamily co-receptor in regulating epithelial cell homeostasis.

Journal Article.  4800 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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