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Mol Cell January 15, 2010; 37 (1): 123-34.
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TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.

Watanabe Y , Itoh S , Goto T , Ohnishi E , Inamitsu M , Itoh F , Satoh K , Wiercinska E , Yang W , Shi L , Tanaka A , Nakano N , Mommaas AM , Shibuya H , Ten Dijke P , Kato M .

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 (TbetaRI)-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 TbetaRI 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.

PubMed ID: 20129061
Article link: Mol Cell

Species referenced: Xenopus
Genes referenced: acvr1b bmpr1b cdkn1a cdkn2b ctnnb1 fgf4 hoxb7 junb mhc2-dab (provisional) myc plg pmepa1 psmd6 runx1 smad1 smad2 smad3 smad4 smad4.2 smad7 tbxt tff3.1 tgfb1 tgfbr1 zfyve9
GO keywords: BMP signaling pathway
Morpholinos: pmepa1 MO1

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