生物谷援引上海上海生命科學(xué)研究院：我科學(xué)家發(fā)現(xiàn)細(xì)胞關(guān)鍵增殖信號(hào)通路的空間調(diào)控新分子
本周,，《美國(guó)國(guó)家科學(xué)院院刊》(Proceedings of the National Academy of Sciences of the United States of America)發(fā)表了中科院上海生命科學(xué)研究院營(yíng)養(yǎng)科學(xué)研究所陳雁研究組關(guān)于ERK信號(hào)通路調(diào)控的最新研究成果。該研究發(fā)現(xiàn)了一個(gè)新的Raf-1調(diào)控蛋白,，第一次揭示了Raf-1的空間調(diào)控方式,，并提示了一種在高爾基體上遏制ERK信號(hào)通路的新機(jī)制，為未來(lái)研究腫瘤細(xì)胞過(guò)度增生的分子機(jī)理進(jìn)而治療癌癥提示了一個(gè)新的思路和新的靶點(diǎn),。
陳雁研究組的博士生馮琳等人發(fā)現(xiàn)了一個(gè)新的ERK信號(hào)通路的負(fù)調(diào)控蛋白,，并將其命名為RKTG(Raf Kinase Trapping to Golgi)。RKTG與已知的脂聯(lián)素受體(AdipoR1和AdipoR2)同屬于PAQR家族,，具有七次跨膜蛋白的特有結(jié)構(gòu),。研究發(fā)現(xiàn)，和定位在質(zhì)膜上的脂聯(lián)素受體有所不同,，RKTG特異定位于高爾基細(xì)胞器上,，并且具有與脂聯(lián)素受體完全不同的功能。RKTG通過(guò)與Raf-1的相互結(jié)合將胞質(zhì)中分布的Raf-1錨定在高爾基體上,，從而干擾了Raf-1與其上游的Ras以及下游的MEK蛋白的結(jié)合,，并且削弱Raf-1激酶的活化，繼而阻礙了Ras將信號(hào)向下游分子傳遞,，最終導(dǎo)致ERK信號(hào)受到抑制,。該結(jié)論在小鼠模型中得到了進(jìn)一步的驗(yàn)證，在RKTG敲除小鼠中ERK活性增強(qiáng),，并且在受到生長(zhǎng)因子刺激時(shí)表現(xiàn)出更強(qiáng)烈,、持續(xù)時(shí)間更長(zhǎng)久的ERK激活。
ERK信號(hào)通路在細(xì)胞增殖和分化等關(guān)鍵過(guò)程中發(fā)揮了重要的作用,。ERK信號(hào)在體內(nèi)受到嚴(yán)格調(diào)控,，細(xì)胞類型不同、刺激因素不同,、激活持續(xù)時(shí)間不同等因素可以產(chǎn)生不同的ERK信號(hào),，導(dǎo)致不同的生物學(xué)效應(yīng)，而其失調(diào)會(huì)導(dǎo)致惡性腫瘤的發(fā)生,。近年來(lái)對(duì)ERK通路的成員,，如RAS、MEK等分子的亞細(xì)胞空間調(diào)控的發(fā)現(xiàn)為進(jìn)一步闡釋ERK信號(hào)復(fù)雜的調(diào)控方式提供了新的思路，然而Raf是否也受到空間調(diào)控卻尚未發(fā)現(xiàn),。馮琳等人的研究發(fā)現(xiàn)了一個(gè)新的Raf-1調(diào)控蛋白，第一次揭示了Raf-1的空間調(diào)控方式,，并提示了一種在高爾基體上遏制ERK信號(hào)通路的新機(jī)制,，為未來(lái)研究腫瘤細(xì)胞過(guò)度增生的分子機(jī)理進(jìn)而治療癌癥提示了一個(gè)新的思路和新的靶點(diǎn)。在實(shí)驗(yàn)過(guò)程中有關(guān)熒光素酶活性檢測(cè)的試劑盒是我國(guó)上?？贫松锟萍加邢薰旧a(chǎn)的（商標(biāo) KenReal）,，國(guó)產(chǎn)熒光素酶試劑盒的質(zhì)量得到了驗(yàn)證和肯定。
該項(xiàng)工作受到中科院百人計(jì)劃,、國(guó)家杰出青年基金,、國(guó)家重大科學(xué)研究計(jì)劃、以及上海市科委的資助,。
原始出處:
Published online before print August 27, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0701298104
Cell Biology
Spatial regulation of Raf kinase signaling by RKTG
( EGF | ERK | Golgi | Raf-1 | Ras | PAQR3 )
Lin Feng, Xiaoduo Xie, Qiurong Ding, Xiaolin Luo, Jing He, Fengjuan Fan, Weizhong Liu, Zhenzhen Wang, and Yan Chen *
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
Edited by Melanie H. Cobb, University of Texas Southwestern Medical Center, Dallas, TX, and approved July 18, 2007 (received for review February 12, 2007)
Subcellular compartmentalization has become an important theme in cell signaling such as spatial regulation of Ras by RasGRP1 and MEK/ERK by Sef. Here, we report spatial regulation of Raf kinase by RKTG (Raf kinase trapping to Golgi). RKTG is a seven-transmembrane protein localized at the Golgi apparatus. RKTG expression inhibits EGF-stimulated ERK and RSK phosphorylation, blocks NGF-mediated PC12 cell differentiation, and antagonizes Ras- and Raf-1-stimulated Elk-1 transactivation. Through interaction with Raf-1, RKTG changes the localization of Raf-1 from cytoplasm to the Golgi apparatus, blocks EGF-stimulated Raf-1 membrane translocation, and reduces the interaction of Raf-1 with Ras and MEK1. In RKTG-null mice, the basal ERK phosphorylation level is increased in the brain and liver. In RKTG-deleted mouse embryonic fibroblasts, EGF-induced ERK phosphorylation is enhanced. Collectively, our results reveal a paradigm of spatial regulation of Raf kinase by RKTG via sequestrating Raf-1 to the Golgi apparatus and thereby inhibiting the ERK signaling pathway.
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