Nuclear protein trafficking requires the soluble transport factor RanBP1. The subcellular distribution of RanBP1 is dynamic, as the protein shuttles between the nucleus and cytoplasm. To date, the signaling pathways regulating RanBP1 subcellular localization are poorly understood. During interphase, RanBP1 resides mostly in the cytoplasm. We show here that oxidative stress concentrates RanBP1 in the nucleus, and our study defines the underlying mechanisms. Specifically, RanBP1’s cysteine residues are not essential for its oxidant-induced relocation. Furthermore, our pharmacological approaches uncover that signaling mediated by epidermal growth factor receptor (EGFR) and protein kinase A (PKA) control RanBP1 localization during stress. In particular, pharmacological inhibitors of EGFR or PKA diminish the oxidant-dependent relocation of RanBP1. Mutant analysis identified serine 60 and tyrosine 103 as regulators of RanBP1 nuclear accumulation during oxidant exposure. Taken together, our results define RanBP1 as a target of oxidative stress and a downstream effector of EGFR and PKA signaling routes. This positions RanBP1 at the intersection of important cellular signaling circuits.

中文翻译：

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通过 EGFR 和 PKA 途径的氧化应激和信号传导汇聚于核转运因子 RanBP1

核蛋白运输需要可溶性转运因子 RanBP1。 RanBP1 的亚细胞分布是动态的，因为蛋白质在细胞核和细胞质之间穿梭。迄今为止，人们对调节 RanBP1 亚细胞定位的信号通路知之甚少。在间期期间，RanBP1 主要存在于细胞质中。我们在此表明​​氧化应激使 RanBP1 集中在细胞核中，并且我们的研究定义了潜在的机制。具体来说，RanBP1 的半胱氨酸残基对于其氧化剂诱导的重定位并不是必需的。此外，我们的药理学方法发现，表皮生长因子受体 (EGFR) 和蛋白激酶 A (PKA) 介导的信号传导在应激期间控制 RanBP1 定位。特别是，EGFR 或 PKA 的药理学抑制剂可减少 RanBP1 的氧化剂依赖性重新定位。突变分析确定丝氨酸 60 和酪氨酸 103 是氧化剂暴露期间 RanBP1 核积累的调节因子。综上所述，我们的结果将 RanBP1 定义为氧化应激的靶点以及 EGFR 和 PKA 信号通路的下游效应器。这将 RanBP1 置于重要的细胞信号通路的交叉点。