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TMEPAI, a transmembrane TGF-β-inducible protein, sequesters Smad proteins in TGF-β signaling

Susumu Itoh¹, Yukihide Watanabe¹, Kiyotoshi Satoh², Masako Inamitsu¹, Liang Shi¹, Naoko Nakano¹, Aya Tanaka¹, Eliza Wiercinska³, Hiroshi Shibuya², Peter ten Dijke³ & Mitsuyasu Kato¹

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1. Graduate School of Comprehensive Human Sciences, University of Tsukuba, Department of Experimental Pathology
2. Medical Research Institute, Tokyo Medical and Dental University, Department of Molecular Cell Biology
3. Leiden University Medical Center, Department of Molecular Cell Biology

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Document Type:

Manuscript

Date:

Received 07 December 2007 04:05 UTC; Posted 07 December 2007

Subjects:

Cancer, Molecular Cell Biology

Tags:

• Transforming growth factor-β signaling regulation
• Xenopus embryos
• mammalian cells
• Smads

Abstract:

Transforming growth factor-β (TGF-β) is a multifunctional cytokine of key importance for controlling embryogenesis and tissue homeostasis. How TGF-β signals are attenuated and terminated is not well understood. Here, we show that TMEPAI, a direct target gene of TGF-β signaling, antagonizes TGF-β signaling by interfering with TGF-β type I receptor (TβRI)-induced R-Smad phosphorylation. TMEPAI can directly interact with R-Smads via a Smad interaction motif (SIM). TMEPAI competes with Smad anchor for receptor activation (SARA) for R-Smad binding, thereby sequestering R-Smads from TβRI kinase activation. In mammalian cells, ectopic expression of TMEPAI inhibited TGF-β-induced PAI-1 production, whereas specific siRNA-mediated knockdown of TMEPAI expression potentiated TGF-β-induced Smad2 phosphorylation and cellular responsiveness by TGF-β. Consistently, TMEPAI inhibits activin-mediated mesoderm formation in Xenopus embryos. Taken together, TMEPAI participates in a negative feedback loop to control the duration and intensity of TGF-β signaling.

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1 comment

ceshi chen on 23 July 2009 14:08 UTC

Nice work!

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Itoh, Susumu, Watanabe, Yukihide, Satoh, Kiyotoshi, Inamitsu, Masako, Shi, Liang, Nakano, Naoko, Tanaka, Aya, Wiercinska, Eliza, Shibuya, Hiroshi, ten Dijke, Peter, and Kato, Mitsuyasu. TMEPAI, a transmembrane TGF-β-inducible protein, sequesters Smad proteins in TGF-β signaling. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2007.1403.1> (2007)

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