Ras信號通路是膜受體信號向細胞內(nèi)傳遞的重要途徑,。除了在癌癥的發(fā)生發(fā)展過程中發(fā)揮重要作用外,，Ras信號通路參與調(diào)控了細胞一系列的基本生物學活動，包括增殖,、凋亡,、分化和衰老等。Ras信號通路的調(diào)控相當復雜,。
最近的研究發(fā)現(xiàn),，該信號通路在不同亞細胞位置的激活可能會導致完全不同的生物學效應，這種現(xiàn)象被稱為房室化調(diào)控（Compartmentalization）,。比如Ras在質(zhì)膜被激活時,，其下游ERK的激活是瞬時且短暫的；而Ras在高爾基體被激活時,，其下游ERK的激活是延時并持續(xù)的,。但目前對于Ras信號通路在高爾基體上的調(diào)控機制卻知之甚少。
中科院上海生命科學研究院營養(yǎng)所陳雁研究組的博士生金婷,、丁秋蓉等人發(fā)現(xiàn)了能特異性調(diào)節(jié)Ras信號通路在高爾基上活化的全新因子,。PAQR10和PAQR11是定位在高爾基體上的膜蛋白，能夠和Ras相互作用,，增加其在高爾基體上的定位,，并且在高爾基體上激活Ras，從而增強并且延長Ras的下游信號,。進一步的研究發(fā)現(xiàn),，PAQR10/11能與RasGRP1（一個能在高爾基體上激活Ras的瓜氨酸交換因子）結合，并增強其在高爾基體上的定位,。結構域功能分析實驗證實,，RasGRP1的C1結構域?qū)τ赑AQR10/11的結合是必需且充分的。另外,，研究發(fā)現(xiàn)PAQR10/11能促進PC12細胞的分化,，進一步證實PAQR10/11調(diào)節(jié)的Ras信號通路是延時并持續(xù)的。
該研究第一次揭示了PAQR10/11在空間上對Ras信號通路的調(diào)控及生物學效應,，對于Ras在高爾基體上的激活增加了全新的認識,，并為進一步闡述PAQR家族其他成員的功能帶來了啟發(fā),。
上述結果近日在Cell Research在線發(fā)表,。該項研究得到科技部和國家自然科學基金委的資助,。（生物谷 Bioon.com）
doi:10.1038/cr.2011.161
PMC:
PMID:
PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus.
Jin T, Ding Q, Huang H, Xu D, Jiang Y, Zhou B, Li Z, Jiang X, He J, Liu W, Zhang Y, Pan Y, Wang Z, Thomas WG, Chen Y.
Ras plays a pivotal role in many cellular activities, and its subcellular compartmentalization provides spatial and temporal selectivity. Here we report a mode of spatial regulation of Ras signaling in the Golgi apparatus by two highly homologous proteins PAQR10 and PAQR11 of the progestin and AdipoQ receptors family. PAQR10 and PAQR11 are exclusively localized in the Golgi apparatus. Overexpression of PAQR10/PAQR11 stimulates basal and EGF-induced ERK phosphorylation and increases the expression of ERK target genes in a dose-dependent manner. Overexpression of PAQR10/PAQR11 markedly elevates Golgi localization of HRas, NRas and KRas4A, but not KRas4B. PAQR10 and PAQR11 can also interact with HRas, NRas and KRas4A, but not KRas4B. The increased Ras protein at the Golgi apparatus by overexpression of PAQR10/PAQR11 is in an active state. Consistently, knockdown of PAQR10 and PAQR11 reduces EGF-stimulated ERK phosphorylation and Ras activation at the Golgi apparatus. Intriguingly, PAQR10 and PAQR11 are able to interact with RasGRP1, a guanine nucleotide exchange protein of Ras, and increase Golgi localization of RasGRP1. The C1 domain of RasGRP1 is both necessary and sufficient for the interaction of RasGRP1 with PAQR10/PAQR11. The simulation of ERK phosphorylation by overexpressed PAQR10/PAQR11 is abrogated by downregulation of RasGRP1. Furthermore, differentiation of PC12 cells is significantly enhanced by overexpression of PAQR10/PAQR11. Collectively, this study uncovers a new paradigm of spatial regulation of Ras signaling in the Golgi apparatus by PAQR10 and PAQR11.Cell Research advance online publication 4 October 2011; doi: 10.1038/cr.2011.161.
