SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling
SPSB1-mediated HnRNP A1 ubiquitylation regulates alternative splicing and cell migration in EGF signaling
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SPSB1介导的HnRNP A1泛素化调节EGF信号传导中的选择性剪接和细胞迁移
DOI：
10.1038/cr.2017.7
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发表时间：
2017-04-01
期刊：
影响因子：
44.1
通讯作者：
Hui, Jingyi
中科院分区：
文献类型：
--
作者：
Wang, Feng;Fu, Xing;Hui, Jingyi
已有研究表明，细胞外信号会影响前体信使核糖核酸（pre - mRNA）的可变剪接；然而，信号诱导剪接调控的分子机制和生物学意义在很大程度上仍不明确。在此，我们报告称表皮生长因子（EGF）通过对一种知名剪接调节因子——异质核糖核蛋白A1（hnRNP A1）进行泛素化修饰，从而诱导剪接变化。EGF信号传导会上调一种E3泛素（Ub）连接酶衔接蛋白——含SPRY结构域的细胞因子信号抑制因子盒蛋白1（SPSB1），该蛋白会募集延伸蛋白B/C - 库林复合物，将赖氨酸29连接的多聚泛素链连接到hnRNP A1上。重要的是，SPSB1以及hnRNP A1的泛素化在EGF驱动的细胞迁移中起着关键作用。从机制上讲，EGF诱导的hnRNP A1泛素化，连同丝氨酸/精氨酸富集蛋白激酶（SRPKs）的激活，会导致Rac1剪接异构体Rac1b的上调，从而促进细胞运动。这些发现揭示了EGF/表皮生长因子受体（EGFR）信号通路中蛋白质泛素化与可变剪接之间一种新的相互作用，并确定了一条在调节细胞迁移中起作用的新的EGF/SPSB1/hnRNP A1/Rac1轴，这可能对癌症治疗具有重要意义。
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.