ABSTRACT

The proper segregation of basic elements such as the compartmentalization of the genome and the shuttling of macromolecules between the nucleus and the cytoplasm is a crucial mechanism for homeostasis maintenance in eukaryotic cells. XPO1 (Exportin 1) is the major nuclear export receptor and is required for the export of proteins and RNAs out of the nucleus. STK38 (also known as NDR1) is a Hippo pathway serine/threonine kinase with multifarious functions in normal and cancer cells. In this review, we summarize the history of the discovery of the nucleo/cytoplasmic shuttling of proteins and focus on the major actor of nuclear export: XPO1. After describing the molecular events required for XPO1-mediated nuclear export of proteins, we introduce the Hippo pathway STK38 kinase, synthetize its regulation mechanisms as well as its biological functions in both normal and cancer cells, and finally its intersection with XPO1 biology. We discuss the recently identified mechanism of XPO1 activation by phosphorylation of XPO1_S1055 by STK38 and contextualize this finding according to the biological functions previously reported for both XPO1 and STK38, including the second identity of STK38 as an autophagy regulator. Finally, we phrase this newly identified activation mechanism into the general nuclear export machinery and examine the possible outcomes of nuclear export inhibition in cancer treatment.

摘要

基本元素的适当分离，例如基因组的区室化和大分子在细胞核和细胞质之间的穿梭，是真核细胞内稳态维持的关键机制。XPO1（Exportin 1）是主要的核输出受体，是将蛋白质和 RNA 输出细胞核所必需的。STK38（也称为 NDR1）是一种 Hippo 途径丝氨酸/苏氨酸激酶，在正常细胞和癌细胞中具有多种功能。在这篇综述中，我们总结了蛋白质的核/细胞质穿梭发现的历史，并重点关注核输出的主要参与者：XPO1。在描述了 XPO1 介导的蛋白质核输出所需的分子事件后，我们介绍了 Hippo 通路 STK38 激酶，在正常细胞和癌细胞中综合其调节机制及其生物学功能，最后与 XPO1 生物学交叉。我们讨论了最近通过 STK38 磷酸化 XPO1_S1055 激活 XPO1 的机制，并根据先前报道的 XPO1 和 STK38 的生物学功能将这一发现置于背景下，包括 STK38 作为自噬调节剂的第二个身份。最后，我们将这种新发现的激活机制描述为一般的核输出机制，并检查核输出抑制在癌症治疗中的可能结果。我们讨论了最近通过 STK38 磷酸化 XPO1_S1055 激活 XPO1 的机制，并根据先前报道的 XPO1 和 STK38 的生物学功能将这一发现置于背景下，包括 STK38 作为自噬调节剂的第二个身份。最后，我们将这种新发现的激活机制描述为一般的核输出机制，并检查核输出抑制在癌症治疗中的可能结果。我们讨论了最近通过 STK38 磷酸化 XPO1_S1055 激活 XPO1 的机制，并根据先前报道的 XPO1 和 STK38 的生物学功能将这一发现置于背景下，包括 STK38 作为自噬调节剂的第二个身份。最后，我们将这种新发现的激活机制描述为一般的核输出机制，并检查核输出抑制在癌症治疗中的可能结果。