TMEPAI，一种跨膜 TGF-β诱导蛋白，将 Smad 蛋白从 TGF-β 信号转导的活性参与中隔离出来。

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

机构信息

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

出版信息

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

DOI:10.1016/j.molcel.2009.10.028

PMID:20129061

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.

摘要

转化生长因子-β（TGF-β）是一种多功能细胞因子，对控制胚胎发生和组织动态平衡具有关键作用。TGF-β信号如何减弱和终止尚不清楚。在这里，我们表明 TMEPAI 是 TGF-β信号的直接靶基因，通过干扰 TGF-β 型 I 受体（TbetaRI）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 通过与 Smad 锚蛋白竞争受体激活来与 R-Smad 结合，从而将 R-Smads 从 TbetaRI 激酶激活中隔离出来。在哺乳动物细胞中，TMEPAI 的异位表达抑制了 TGF-β依赖性对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 TMEPAI 表达的特异性敲低延长了 TGF-β诱导的 Smad2 和 Smad3 磷酸化的持续时间，并协同增强了细胞对 TGF-β的反应性。一致地，TMEPAI 抑制了 Xenopus 胚胎中激活素介导的中胚层形成。因此，TMEPAI 参与了一个负反馈回路，以控制 TGF-β/Smad 信号的持续时间和强度。