Membrane targeting of inhibitory Smads through palmitoylation controls TGF-β/BMP signaling.
Membrane targeting of inhibitory Smads through palmitoylation controls TGF-β/BMP signaling.
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通过棕榈酰化抑制性 Smad 的膜靶向控制 TGF-β/BMP 信号传导。
DOI：
10.1073/pnas.1710540114
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发表时间：
2017-12-12
影响因子：
11.1
通讯作者：
Chen D
中科院分区：
文献类型：
--
作者：
Li W;Li W;Zou L;Ji S;Li C;Liu K;Zhang G;Sun Q;Xiao F;Chen D
抑制性Smads(I-Smads)在负调控转化生长因子-β/骨形态发生蛋白信号转导通路中发挥重要作用，从而调控多种细胞和发育过程。最近的研究表明，Smad7是I-Smads的成员之一，在多种癌症类型中都有过表达，其丰度与肿瘤的恶性程度呈正相关。然而，I-Smads在细胞中作用的分子机制仍然知之甚少。在这里，我们展示了果蝇I-Smad，爸爸，通过棕榈酰化进入膜，靶向BMP I型受体泛素化。重要的是，我们发现棕榈酰转移酶dHIP14催化DAD棕榈酰化并拮抗BMP/DPP信号转导。我们的发现揭示了I-Smad控制转化生长因子-β/骨形态发生蛋白信号的机制。转化生长因子-β/骨形态发生蛋白信号通路在控制胚胎发育、组织动态平衡和干细胞调控中发挥着保守的作用。抑制性Smads(I-Smads)主要针对I型受体的泛素化和代谢，对转化生长因子-β/骨形态发生蛋白信号转导起负性调节作用。然而，人们对I-SMADs如何进入膜来执行其功能知之甚少。在这里，我们展示了果蝇I-Smad的爸爸通过棕榈酰化与细胞膜结合，从而靶向BMP I型受体进行泛素化。通过系统的生化分析，我们表征了特定的半胱氨酸(Cys556)，它是爸爸棕榈酰化和膜结合所必需的。此外，我们还证明了果蝇棕榈酰基转移酶dHIP14催化DAD棕榈酰化，从而抑制有效的BMP信号转导。因此，我们的发现揭示了控制转化生长因子-β/骨形态发生蛋白信号活性的抑制性Smads的修饰。
Inhibitory Smads (I-Smads) play important roles to negatively regulate TGF-β/BMP (bone morphogenetic protein) signaling, thus controlling numerous cellular and developmental processes. Recent studies have suggested that Smad7, a member of I-Smads, is overexpressed in numerous cancer types and its abundance is positively correlated to the malignancy. However, the molecular mechanism underlying action of I-Smads in cells remains poorly understood. Here we show that the Drosophila I-Smad, Dad, accesses the membrane via palmitoylation to target the BMP type I receptor for ubiquitination. Importantly, we show that the palmitoyltransferase dHIP14 catalyzes Dad palmitoylation and antagonizes BMP/Dpp signaling. Our findings uncover a mechanism by which I-Smad controls TGF-β/BMP signaling. TGF-β/BMP (bone morphogenetic protein) signaling pathways play conserved roles in controlling embryonic development, tissue homeostasis, and stem cell regulation. Inhibitory Smads (I-Smads) have been shown to negatively regulate TGF-β/BMP signaling by primarily targeting the type I receptors for ubiquitination and turnover. However, little is known about how I-Smads access the membrane to execute their functions. Here we show that Dad, the Drosophila I-Smad, associates with the cellular membrane via palmitoylation, thereby targeting the BMP type I receptor for ubiquitination. By performing systematic biochemistry assays, we characterized the specific cysteine (Cys556) essential for Dad palmitoylation and membrane association. Moreover, we demonstrate that dHIP14, a Drosophila palmitoyl acyl-transferase, catalyzes Dad palmitoylation, thereby inhibiting efficient BMP signaling. Thus, our findings uncover a modification of the inhibitory Smads that controls TGF-β/BMP signaling activity.
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影响因子：
16.8
作者：
Weiss, Alexander;Charbonnier, Enrica;Affolter, Markus
通讯作者：
Affolter, Markus
Ankyrin-G的半胱氨酸70已被S-膜酰化化，并且是膜结构域组装中Ankyrin-G的功能所必需的。
DOI：
10.1074/jbc.m112.417501
发表时间：
2012-12-21
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
He M;Jenkins P;Bennett V
通讯作者：
Bennett V
DOI：
10.1083/jcb.201008160
发表时间：
2010-12-27
期刊：
The Journal of cell biology
影响因子：
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作者：
Salaun C;Greaves J;Chamberlain LH
通讯作者：
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影响因子：
4.8
作者：
Ebisawa, T;Fukuchi, M;Miyazono, K
通讯作者：
Miyazono, K
影响因子：
16
作者：
Kavsak, P;Rasmussen, RK;Wrana, JL
通讯作者：
Wrana, JL