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The type III TGF-beta receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation.

Publication ,  Journal Article
You, HJ; Bruinsma, MW; How, T; Ostrander, JH; Blobe, GC
Published in: Carcinogenesis
December 2007

Transforming growth factor beta (TGFbeta) has an important role as a negative regulator of cellular proliferation. The type III transforming growth factor beta receptor (TbetaRIII) has an emerging role as both a TGFbeta superfamily co-receptor and in mediating signaling through its cytoplasmic domain. In L6 myoblasts, TbetaRIII expression enhanced TGFbeta1-mediated growth inhibition, with this effect mediated, in part, by the TbetaRIII cytoplasmic domain. The effects of TbetaRIII were not due to altered ligand presentation or to differences in Smad2 phosphorylation. Instead, TbetaRIII specifically increased Smad3 phosphorylation, both basal and TGFbeta-stimulated Smad3 nuclear localization and Smad3-dependent activation of reporter genes independent of its cytoplasmic domain. Conversely, SB431542, a type I transforming growth factor beta receptor (TbetaRI) inhibitor, as well as dominant-negative Smad3 specifically and significantly abrogated the effects of TbetaRIII on TGFbeta1-mediated inhibition of proliferation. TbetaRIII also specifically increased p38 phosphorylation, and SB203580, a p38 kinase inhibitor, specifically and significantly abrogated the effects of TbetaRIII/TGFbeta1-mediated inhibition of proliferation in L6 myoblasts and in primary human epithelial cells. Importantly, treatment with the TbetaRI and p38 inhibitors together had additive effects on abrogating TbetaRIII/TGFbeta1-mediated inhibition of proliferation. In a reciprocal manner, short hairpin RNA-mediated knockdown of endogenous TbetaRIII in various human epithelial cells attenuated TGFbeta1-mediated inhibition of proliferation. Taken together, these data demonstrate that TbetaRIII contributes to and enhances TGFbeta-mediated growth inhibition through both TbetaRI/Smad3-dependent and p38 mitogen-activated protein kinase pathways.

Duke Scholars

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

December 2007

Volume

28

Issue

12

Start / End Page

2491 / 2500

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Transforming Growth Factor beta1
  • Smad3 Protein
  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Rats
  • Proteoglycans
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Myoblasts
 

Citation

APA
Chicago
ICMJE
MLA
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You, H. J., Bruinsma, M. W., How, T., Ostrander, J. H., & Blobe, G. C. (2007). The type III TGF-beta receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation. Carcinogenesis, 28(12), 2491–2500. https://doi.org/10.1093/carcin/bgm195
You, Hye Jin, Monique W. Bruinsma, Tam How, Julie H. Ostrander, and Gerard C. Blobe. “The type III TGF-beta receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation.Carcinogenesis 28, no. 12 (December 2007): 2491–2500. https://doi.org/10.1093/carcin/bgm195.
You HJ, Bruinsma MW, How T, Ostrander JH, Blobe GC. The type III TGF-beta receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation. Carcinogenesis. 2007 Dec;28(12):2491–500.
You, Hye Jin, et al. “The type III TGF-beta receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation.Carcinogenesis, vol. 28, no. 12, Dec. 2007, pp. 2491–500. Pubmed, doi:10.1093/carcin/bgm195.
You HJ, Bruinsma MW, How T, Ostrander JH, Blobe GC. The type III TGF-beta receptor signals through both Smad3 and the p38 MAP kinase pathways to contribute to inhibition of cell proliferation. Carcinogenesis. 2007 Dec;28(12):2491–2500.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

December 2007

Volume

28

Issue

12

Start / End Page

2491 / 2500

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Transforming Growth Factor beta1
  • Smad3 Protein
  • Signal Transduction
  • Receptors, Transforming Growth Factor beta
  • Rats
  • Proteoglycans
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Myoblasts