PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus

• Published in: Cell research Vol. 22; no. 4; pp. 661 - 676
• Main Authors: Jin, Ting, Ding, Qiurong, Huang, Heng, Xu, Daqian, Jiang, Yuhui, Zhou, Ben, Li, Zhenghu, Jiang, Xiaomeng, He, Jing, Liu, Weizhong, Zhang, Yixuan, Pan, Yi, Wang, Zhenzhen, Thomas, Walter G, Chen, Yan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2012; Nature Publishing Group
• Subjects: Biomedical and Life Sciences; Cell Biology; Cell Communication - genetics; Cell Compartmentation - genetics; Cell Differentiation - genetics; Differentiation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Extracellular signal-regulated kinase; Gene Expression Regulation; Golgi apparatus; Golgi Apparatus - genetics; Golgi Apparatus - metabolism; guanine nucleotide exchange factor; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; HEK293 Cells; HeLa Cells; Humans; Life Sciences; MAP Kinase Signaling System - genetics; Original; original-article; PC12 Cells; Pheochromocytoma cells; Phosphorylation; progestin; Protein Binding; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Ras; Ras protein; RAS蛋白; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; 介导; 信号; 表皮生长因子; 过度表达; 高尔基体; 鸟嘌呤核苷; Signal transduction; Ras; compartmentalization; Golgi apparatus; ERK
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2011.161

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 PAQRll of the progestin and AdipoQ receptors family. PAQRI0 and PAQRll are exclusively localized in the Golgi apparatus. Overexpression of PAQR10/PAQRll stimulates basal and EGF-induced ERK phosphorylation and increases the expression of ERK target genes in a dose-dependent man- ner. Overexpression of PAQR10/PAQRll markedly elevates Golgi localization of HRas, NRas and KRas4A, but not KRas4B. PAQR10 and PAQRll can also interact with HRas, NRas and KRas4A, but not KRas4B. The increased Ras protein at the Golgi apparatus by overexpression of PAQR10/PAQRll is in an active state. Consistently, knockdown of PAQR10 and PAQRll reduces EGF-stimulated ERK phosphorylation and Ras activation at the Golgi apparatus. Intriguingly, PAQR10 and PAQRll 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/PAQRll. The simulation of ERK phosphorylation by overexpressed PAQR10/ PAQRll is abrogated by downregulation of RasGRP1. Furthermore, differentiation of PC12 cells is significantly enhanced by overexpression of PAQR10/PAQRll. Collectively, this study uncovers a new paradigm of spatial regulation of Ras signaling in the Golgi apparatus by PAQR10 and PAQRll.