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TGF-β 通过一种新颖的受体激活方式磷酸化 SMAD1/5，诱导上皮间质转化。

TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition.

机构信息

Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom.

Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom.

出版信息

Elife. 2018 Jan 29;7:e31756. doi: 10.7554/eLife.31756.

DOI:10.7554/eLife.31756
PMID:29376829
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5832415/
Abstract

The best characterized signaling pathway downstream of transforming growth factor β (TGF-β) is through SMAD2 and SMAD3. However, TGF-β also induces phosphorylation of SMAD1 and SMAD5, but the mechanism of this phosphorylation and its functional relevance is not known. Here, we show that TGF-β-induced SMAD1/5 phosphorylation requires members of two classes of type I receptor, TGFBR1 and ACVR1, and establish a new paradigm for receptor activation where TGFBR1 phosphorylates and activates ACVR1, which phosphorylates SMAD1/5. We demonstrate the biological significance of this pathway by showing that approximately a quarter of the TGF-β-induced transcriptome depends on SMAD1/5 signaling, with major early transcriptional targets being the genes. Finally, we show that TGF-β-induced epithelial-to-mesenchymal transition requires signaling via both the SMAD3 and SMAD1/5 pathways, with SMAD1/5 signaling being essential to induce ID1. Therefore, combinatorial signaling via both SMAD pathways is essential for the full TGF-β-induced transcriptional program and physiological responses.

摘要

转化生长因子 β（TGF-β）下游最具特征性的信号通路是通过 SMAD2 和 SMAD3。然而，TGF-β 还诱导 SMAD1 和 SMAD5 的磷酸化，但这种磷酸化的机制及其功能相关性尚不清楚。在这里，我们表明 TGF-β 诱导的 SMAD1/5 磷酸化需要两类 I 型受体 TGFBR1 和 ACVR1 的成员，并且建立了一个新的受体激活范例，其中 TGFBR1 磷酸化并激活 ACVR1，ACVR1 磷酸化 SMAD1/5。我们通过表明大约四分之一的 TGF-β 诱导的转录组依赖于 SMAD1/5 信号转导来证明该途径的生物学意义，其主要的早期转录靶标是基因。最后，我们表明 TGF-β 诱导的上皮-间充质转化需要通过 SMAD3 和 SMAD1/5 途径进行信号转导，SMAD1/5 信号转导对于诱导 ID1 是必需的。因此，两种 SMAD 途径的组合信号对于 TGF-β 诱导的完整转录程序和生理反应是必不可少的。

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