TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling

Mol Cell. 2010 Jan 15;37(1):123-34. doi: 10.1016/j.molcel.2009.10.028.

Yukihide Watanabe ¹, 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

Affiliations

Affiliation

1 Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

PMID: 20129061 DOI: 10.1016/j.molcel.2009.10.028

Abstract

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.

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