Ras信号通路是膜受体信号向细胞内传递的重要途径。除了在癌症的发生发展过程中发挥重要作用外，Ras信号通路参与调控了细胞一系列的基本生物学活动，包括增殖、凋亡、分化和衰老等。Ras信号通路的调控相当复杂。
最近的研究发现，该信号通路在不同亚细胞位置的激活可能会导致完全不同的生物学效应，这种现象被称为房室化调控（Compartmentalization）。比如Ras在质膜被激活时，其下游ERK的激活是瞬时且短暂的；而Ras在高尔基体被激活时，其下游ERK的激活是延时并持续的。但目前对于Ras信号通路在高尔基体上的调控机制却知之甚少。
中科院上海生命科学研究院营养所陈雁研究组的博士生金婷、丁秋蓉等人发现了能特异性调节Ras信号通路在高尔基上活化的全新因子。PAQR10和PAQR11是定位在高尔基体上的膜蛋白，能够和Ras相互作用，增加其在高尔基体上的定位，并且在高尔基体上激活Ras，从而增强并且延长Ras的下游信号。进一步的研究发现，PAQR10/11能与RasGRP1（一个能在高尔基体上激活Ras的瓜氨酸交换因子）结合，并增强其在高尔基体上的定位。结构域功能分析实验证实，RasGRP1的C1结构域对于PAQR10/11的结合是必需且充分的。另外，研究发现PAQR10/11能促进PC12细胞的分化，进一步证实PAQR10/11调节的Ras信号通路是延时并持续的。
该研究第一次揭示了PAQR10/11在空间上对Ras信号通路的调控及生物学效应，对于Ras在高尔基体上的激活增加了全新的认识，并为进一步阐述PAQR家族其他成员的功能带来了启发。
上述结果近日在Cell Research在线发表。该项研究得到科技部和国家自然科学基金委的资助。（生物谷 Bioon.com）
doi:10.1038/cr.2011.161
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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.
