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

Publication ,  Journal Article
You, HJ; How, T; Blobe, GC
Published in: Carcinogenesis
August 2009

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

Duke Scholars

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

August 2009

Volume

30

Issue

8

Start / End Page

1281 / 1287

Location

England

Related Subject Headings

  • beta-Arrestins
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Transfection
  • Receptors, Transforming Growth Factor beta
  • RNA, Small Interfering
  • Proteoglycans
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Luciferases
 

Citation

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You, H. J., How, T., & Blobe, G. C. (2009). The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2. Carcinogenesis, 30(8), 1281–1287. https://doi.org/10.1093/carcin/bgp071
You, Hye Jin, Tam How, and Gerard C. Blobe. “The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2.Carcinogenesis 30, no. 8 (August 2009): 1281–87. https://doi.org/10.1093/carcin/bgp071.
You, Hye Jin, et al. “The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2.Carcinogenesis, vol. 30, no. 8, Aug. 2009, pp. 1281–87. Pubmed, doi:10.1093/carcin/bgp071.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

August 2009

Volume

30

Issue

8

Start / End Page

1281 / 1287

Location

England

Related Subject Headings

  • beta-Arrestins
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Transfection
  • Receptors, Transforming Growth Factor beta
  • RNA, Small Interfering
  • Proteoglycans
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Luciferases