title: SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences, Shanghai 201602, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Fu
authors.affiliation: Key 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.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Jia
authors.affiliation: Key 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.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Key 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.
authors.forename: Ronggui
authors.initials: R
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Hui
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D000075065:Elongin / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1 / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012322:RNA Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D044842:Cullin Proteins; D000075065:Elongin; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D012322:RNA Precursors; D012333:RNA, Messenger; C000602043:SPSB1 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D025821:Polyubiquitin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020830:rac1 GTP-Binding Protein; D008239:Lysine