TMEPAI, a Transmembrane TGF-β-Inducible Protein, Sequesters Smad Proteins from Active Participation in TGF-β Signaling

• DOI: 10.1016/j.molcel.2009.10.028
• Publication Date: 2010-01-15T09:28:34Z
• Authors: Yukihide Watanabe; Susumu Itoh; Toshiyasu Goto; Eriko Ohnishi; Masako Inamitsu; Fumiko Itoh; Kiyotoshi Satoh; Eliza Wiercinska; Weiwen Yang; Liang Shi; Aya Tanaka; Naoko Nakano; A. Mieke Mommaas; Hiroshi Shibuya; Peter ten Dijke; Mitsuyasu Kato
• Keywords: JUNB; Smad2 Protein; Ectopic expression

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.