title: PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus.
abstract: 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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Jin
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Ding
authors.forename: Heng
authors.initials: H
authors.lastname: Huang
authors.forename: Daqian
authors.initials: D
authors.lastname: Xu
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ben
authors.initials: B
authors.lastname: Zhou
authors.forename: Zhenghu
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Weizhong
authors.initials: W
authors.lastname: Liu
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Walter G
authors.initials: WG
authors.lastname: Thomas
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D002450:Cell Communication / Q000235:genetics; D002451:Cell Compartmentation / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C572580:MMD2 protein, human; C491790:RASGRP1 protein, human; D011956:Receptors, Cell Surface; D016283:Proto-Oncogene Proteins p21(ras)