TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.
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.
Watanabe
Yukihide
Y
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Itoh
Susumu
S
Goto
Toshiyasu
T
Ohnishi
Eriko
E
Inamitsu
Masako
M
Itoh
Fumiko
F
Satoh
Kiyotoshi
K
Wiercinska
Eliza
E
Yang
Weiwen
W
Shi
Liang
L
Tanaka
Aya
A
Nakano
Naoko
N
Mommaas
A Mieke
AM
Shibuya
Hiroshi
H
Ten Dijke
Peter
P
Kato
Mitsuyasu
M
D028341:Activins / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004625:Embryo, Nonmammalian / Q000378:metabolism; D047108:Embryonic Development; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000254:growth & development; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014981:Xenopus
D008565:Membrane Proteins; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D028341:Activins