SPSBl-mediated HnRNP A1 alternative splicing and cell ubiquitylation regulates migration in EGF signaling  

作　　者：Feng Wang Xing Fu Peng Chen Ping Wu Xiaojuan Fan Na Li Hong Zhu Ting-Ting Jia Hongbin Ji Zefeng Wang Catherine C L Wong Ronggui Hu Jingyi Hui 

机构地区：[1]State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences University of Chinese Academy of Sciences, Shanghai 200031, China [2]Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences, Shanghai 201602, China [3]Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Ceil Biology, Chinese Academy of Sciences, Shanghai 200031, China [4]National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China [5]Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China [6]Key Lab of Computational Biology, CAS Center for Excellence in Molecular Cell Science, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai 200031, China

出　　处：《Cell Research》2017年第4期540-558,共19页细胞研究（英文版）

基　　金：We thank Drs Xiang-Dong Fu, Zhongsheng You and Min Wei for critical reading of the manuscript and invaluable suggestions, and all the members of Jingyi Hui and Ronggui Hu＇s laboratories, especially Jiancheng Yu, Xiaojuan Yang and Jie Ye for technical assistance. We are grateful to Dr Xianghui Yu for generously providing us expression plasmids for Elongin B/C, Cu15 and RBX1/2, and to Dr Daming Gao for antilongin B/C antibodies. This work was supported by National Natural Science Foundation of China （31570820, 31661143035 and 31370787） to JH and （31270828, 31470770 and 81525019） to RH and by the National Basic Research Program of China （2012CB910800 and 2013CB910900） to RH. RH was also supported by Shanghai Institute of Organic Chemistry, CAS, and the Instrument Developing Project of CAS （YZ201339）.

摘　　要：ExtraceUular signals have been shown to impact on alternative pre-mRNA splicing; however, the molecular mech- anisms and biological significance of signal-induced splicing regulation remain largely unknown. Here, we report that epidermal growth factor （EGF） induces splicing changes through ubiquitylation of a well-known splicing regula- tor, hnRNP A1. EGF signaling upregulates an E3 ubiquitin （Ub） ligase adaptor, SPRY domain-containing SOCS box protein 1 （SPSB1）, which recruits Elongin B/C-Cullin complexes to conjugate lysine 29-1inked polyUb chains onto hnRNP A1. Importantly, SPSB1 and ubiquitylation of hnRNP A1 have a critical role in EGF-driven cell migration. Mechanistically, EGF-induced ubiquitylation of hnRNPA1 together with the activation of SR protein kinases （SRPKs） results in the upregulation of a Racl splicing isoform, Raclb, to promote cell motility. These findings unravel a novel crosstalk between protein ubiquitylation and alternative splicing in EGF/EGF receptor signaling, and identify a new EGF/SPSB1/hnRNP A1/Racl axis in modulating cell migration, which may have important implications for cancer treatment.

关 键 词：alternative splicing EGF signaling hnRNP A1 protein ubiquitylation RACL SPSB1 

分 类 号：Q[生物学]