Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School , Boston, USA.
Inserm U830, Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University , Paris, France.
Cell Cycle. 2020 Nov;19(22):2982-2995. doi: 10.1080/15384101.2020.1826619. Epub 2020 Oct 5.
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.
正确分隔基本元素，如基因组的区室化和大分子在核和细胞质之间的穿梭，是真核细胞维持内稳态的关键机制。XPO1（Exportin 1）是主要的核输出受体，是蛋白质和 RNA 从核内输出所必需的。STK38（也称为 NDR1）是 Hippo 通路丝氨酸/苏氨酸激酶，在正常和癌细胞中有多种功能。在这篇综述中，我们总结了蛋白质核质穿梭发现的历史，重点介绍了核输出的主要因子：XPO1。在描述了 XPO1 介导的蛋白质核输出所需的分子事件之后，我们介绍了 Hippo 通路 STK38 激酶，综合了其调节机制及其在正常和癌细胞中的生物学功能，最后介绍了其与 XPO1 生物学的交叉点。我们讨论了最近发现的由 STK38 磷酸化 XPO1_S1055 激活 XPO1 的机制，并根据 XPO1 和 STK38 先前报道的生物学功能，包括 STK38 作为自噬调节剂的第二个身份，将这一发现置于背景中。最后，我们将这个新发现的激活机制纳入一般的核输出机制，并研究核输出抑制在癌症治疗中的可能结果。
