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

摘要

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 upregnlation 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.