來自中國科學(xué)院生物物理所,、武漢病毒研究所、北京生命科學(xué)研究院等處的研究人員在新研究中證實(shí),，肌微管素相關(guān)蛋白4(MTMR4)通過去磷酸化Smad蛋白抑制了BMP/Dpp信號(hào),，相關(guān)論文發(fā)表在1月4日的《生物化學(xué)期刊》（JBC）上。
中科院生物物理所的唐宏研究員和潘磊博士為這篇文章的共同通訊作者,。唐宏研究員主要從事冠狀病毒,、肝炎病毒感染的天然免疫應(yīng)答的分子機(jī)制，以及T細(xì)胞對(duì)炎性反應(yīng)的調(diào)控機(jī)制研究,。
轉(zhuǎn)化生長因子(transforming growth factor β, TGF-β)超家族包括近30種與生長和分化相關(guān)的分子成員,主要由骨形成蛋白(bone morphogenetic protein,BMP),、activins和TGF-βs三個(gè)亞家族組成。研究表明, 該家族成員在三胚層命運(yùn)決定,、以后的各組織器官發(fā)育形成, 以及癌癥發(fā)生過程中均發(fā)揮關(guān)鍵的調(diào)控作用,。作為TGF-β超家族的成員之一, BMP最早被發(fā)現(xiàn)是與骨骼系統(tǒng)的發(fā)育形成過程密切相關(guān)，越來越多的研究表明BMP信號(hào)通路通過調(diào)節(jié)一系列下游基因的活性,，控制著諸如中胚層形成,、神經(jīng)系統(tǒng)分化、牙齒和骨骼發(fā)育以及癌癥發(fā)生等許多重要的生物學(xué)過程,。盡管近年來在不同層面鑒別出了多個(gè)調(diào)控因子,，對(duì)于BMP信號(hào)穩(wěn)態(tài)機(jī)制仍知之甚少。
在這篇文章中,，研究人員證實(shí)MTMR4,，一種具有FYVE結(jié)構(gòu)域的雙特異性蛋白磷酸酶(DUSP)，在細(xì)胞質(zhì)中優(yōu)先結(jié)合并去磷酸化活化的R-Smads,。由此,，BMPs介導(dǎo)的轉(zhuǎn)錄激活受到MTMR4表達(dá)水平和內(nèi)在磷酸酶活性的嚴(yán)密控制。更重要的是,，研究人員發(fā)現(xiàn)異位表達(dá)MTMR4或是它的果蠅同源物CG3632,，與BMP/Dpp信號(hào)軸發(fā)生了遺傳互作。由此，MTMR4與果蠅BMP信號(hào)中唯一的R-Smad——Mad發(fā)生相互作用并使其去磷酸化,，從而影響了Mad靶基因的表達(dá),。
研究結(jié)果表明MTMR4是BMP/Dpp信號(hào)穩(wěn)態(tài)的一個(gè)重要的負(fù)調(diào)控因子。(生物谷Bioon.com)
DOI:10.1074/jbc.M112.413856
PMC:
PMID:
Myotubularin-related Protein 4 (MTMR4) Attenuates BMP/Dpp Signaling by Dephosphorylation of Smad Proteins
Junjing Yu (俞 珺璟)‡§,1, Xiaomeng He (賀 曉萌)‡¶,1, Ye-Guang Chen (陳 曄光)‖, Yan Hao (郝 巖)‡¶, Shuo Yang (楊 爍)‡¶, Lei Wang (王 磊)¶,**, Lei Pan (潘 磊)‡§,2 and Hong Tang (唐 宏)‡§,**,3
Bone morphogenetic proteins (BMPs) signaling essentially regulates a wide range of biological responses. Although multiple regulators at different layers of the receptor-effectors axis have been identified, the mechanisms of homeostatic BMP signaling remain vague. Herein we demonstrated that myotubularin-related protein 4 (MTMR4), a FYVE domain-containing dual-specificity protein phosphatase (DUSP), preferentially associated with and dephosphorylated the activated R-Smads in cytoplasm, which is a critical checkpoint in BMP signal transduction. Therefore, transcriptional activation by BMPs was tightly controlled by the expression level and the intrinsic phosphatase activity of MTMR4. More profoundly, ectopic expression of MTMR4 or its Drosophila homolog CG3632 genetically interacted with BMP/Dpp signaling axis in regulation of the vein development of Drosophila wings. By doing so, MTMR4 could interact with and dephosphorylate Mothers against Decapentaplegic (Mad), the sole R-Smad in Drosophila BMP pathway, and hence affected the target genes expression of Mad. In conclusion, this study has suggested that MTMR4 is a necessary negative modulator for the homeostasis of BMP/Dpp signaling.
