Journal
MOLECULAR CELL
Volume 37, Issue 1, Pages 123-134Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2009.10.028
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Funding
- Ministry of Education, Culture, Sports, Science and Technology [17390073, 20012007, 21590328]
- Japan Society for the Promotion of Science
- Long-range Research initiative (LPI)
- Japan Chemical Industry Association (JCIA)
- AstraZeneca Research
- Kowa Life Science Foundation
- Kato Memorial Bioscience Foundation
- Dutch Cancer Society EC
- Grants-in-Aid for Scientific Research [21590328, 17390073, 20012007] Funding Source: KAKEN
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Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine of key importance for controlling embryogenesis and tissue homeostasis. How TGF-beta signals are attenuated and terminated is not well understood. Here, we show that TMEPAI, a direct target gene of TGF-beta signaling, antagonizes TGF-beta signaling by interfering with TGF-beta type I receptor (T beta RI)-induced R-Smad phosphorylation. TMEPAI can directly interact with R-Smads via a Smad interaction motif. TMEPAI competes with Smad anchor for receptor activation for R-Smad binding, thereby sequestering R-Smads from T beta RI kinase activation. In mammalian cells, ectopic expression of TMEPAI inhibited TGF-beta-dependent regulation of plasminogen activator inhibitor-1, JunB, cyclin-dependent kinase inhibitors, and c-myc expression, whereas specific knockdown of TMEPAI expression prolonged duration of TGF-beta-induced Smad2 and Smad3 phosphorylation and concomitantly potentiated cellular responsiveness to TGF-beta. Consistently, TMEPAI inhibits activin-mediated mesoderm formation in Xenopus embryos. Therefore, TMEPAI participates in a negative feedback loop to control the duration and intensity of TGF-beta/Smad signaling.
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