Volume 27, No 4, Apr 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 4, April 2017: 540-558

ORIGINAL ARTICLES

SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling

Feng Wang¹, Xing Fu², Peng Chen³, Ping Wu^4,5, Xiaojuan Fan⁶, Na Li¹, Hong Zhu¹, Ting-Ting Jia¹, Hongbin Ji³, Zefeng Wang⁶, Catherine C L Wong^4,5, Ronggui Hu³ and Jingyi Hui¹

¹State 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
²Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences, Shanghai 201602, China
³Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
⁴National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
⁵Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China
⁶Key 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 Correspondence: Jingyi Hui, E-mail: jyhui@sibcb.ac.cn; Ronggui Hu,(coryhu@sibcb.ac.cn)

Extracellular signals have been shown to impact on alternative pre-mRNA splicing; however, the molecular mechanisms 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 regulator, 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-linked 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 hnRNP A1 together with the activation of SR protein kinases (SRPKs) results in the upregulation of a Rac1 splicing isoform, Rac1b, 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/Rac1 axis in modulating cell migration, which may have important implications for cancer treatment.

10.1038/cr.2017.7

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