| RRC ID |
28590
|
| Author |
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.
|
| Title |
TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.
|
| Journal |
Mol Cell
|
| 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.
|
| Volume |
37(1)
|
| Pages |
123-34
|
| Published |
2010-1-15
|
| DOI |
10.1016/j.molcel.2009.10.028
|
| PII |
S1097-2765(09)00965-4
|
| PMID |
20129061
|
| MeSH |
Activins / metabolism
Animals
COS Cells
Cell Line
Chlorocebus aethiops
Embryo, Nonmammalian / metabolism
Embryonic Development
Humans
Membrane Proteins / chemistry
Membrane Proteins / genetics
Membrane Proteins / physiology*
Mesoderm / growth & development
Mice
Models, Biological
NIH 3T3 Cells
RNA, Messenger / metabolism
Signal Transduction*
Smad Proteins / metabolism*
Transforming Growth Factor beta / metabolism*
Xenopus
|
| IF |
15.584
|
| Times Cited |
98
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| Resource |
| DNA material |
pCMVmmTMEPAI (RDB08015)
pCMVhsTMEPAIa (RDB08016)
pCMVhsTMEPAIb (RDB08017)
pCMVhsTMEPAIc (RDB08018) |
