TMEPAI, a Transmembrane TGF-β-Inducible Protein, Sequesters Smad Proteins from Active Participation in TGF-β Signaling
TMEPAI, a Transmembrane TGF-β-Inducible Protein, Sequesters Smad Proteins from Active Participation in TGF-β Signaling
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DOI：
10.1016/j.molcel.2009.10.028
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发表时间：
2010-01-15
期刊：
影响因子：
16
通讯作者：
Kato, Mitsuyasu
中科院分区：
文献类型：
--
作者：
Watanabe, Yukihide;Itoh, Susumu;Kato, Mitsuyasu
转化生长因子-β（TGF-β）是一种多功能细胞因子，对于控制胚胎发生和组织稳态至关重要。TGF-β信号是如何衰减和终止的还不清楚。在这里，我们表明TMEPAI，TGF-β信号的直接靶基因，通过干扰TGF-β I型受体（T β RI）诱导的R-Smad磷酸化来拮抗TGF-β信号。TMEPAI可以通过Smad相互作用基序直接与R-Smads相互作用。TMEPAI与Smad锚竞争R-Smad结合的受体活化，从而隔离R-Smad与T β RI激酶活化。在哺乳动物细胞中，TMEPAI的异位表达抑制了TGF-β依赖的纤溶酶原激活物抑制剂-1、JunB、细胞周期蛋白依赖性激酶抑制剂和c-myc表达的调节，而特异性敲除TMEPAI表达延长了TGF-β诱导的Smad 2和Smad 3磷酸化的持续时间，并伴随着增强了细胞对TGF-β的反应性。因此，TMEPAI抑制激活素介导的非洲爪蟾胚胎中的中胚层形成。因此，TMEPAI参与负反馈回路以控制TGF-β/Smad信号传导的持续时间和强度。
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 (T beta RI)-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 T beta RI 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.