经典Wnt信号通路中β-catenin在细胞核内外分布的调控机制及潜在治疗靶点的研究进展  

Research progress on the mechanism regulating the cellular sublocalization of β-catenin and potential associated therapeutic targets in canonical Wnt signaling pathway

作　　者：顾嘉伟 牛耿明 柯重伟 GU Jia-wei;NIU Geng-ming;KE Chong-wei(Department of General Surgery,Shanghai Fifth People's Hospital,Fudan University,Shanghai 200240,China)

机构地区：[1]复旦大学附属上海市第五人民医院普外科,上海200240

出　　处：《复旦学报（医学版）》2022年第2期300-308,共9页Fudan University Journal of Medical Sciences

基　　金：上海市闵行区大学科建设项目(2020MWDXK02)。

摘　　要：经典Wnt信号通路在肿瘤细胞的增殖分化中发挥重要作用,该信号通路中的核心蛋白分子β-catenin介导信号从细胞质传递到细胞核,并在核内参与组成转录复合体,激活下游靶基因转录。β-catenin进入细胞核内是其激活下游转录因子的重要前提,其出入细胞核的方式尚未完全解析。β-catenin入核方式主要为利用经典入核途径关键蛋白直接入核及通过“分子伴侣”协助入核,而出核方式主要为依赖染色体维持区域1(chromosome maintenance region 1,CRM1)的出核途径。细胞膜上的钙黏蛋白、细胞质内的降解复合体相关蛋白及细胞核内的转录复合体相关蛋白等均可导致β-catenin滞留,从而影响其在细胞核内外的分布。在不改变细胞内β-catenin总量的情况下,通过减少β-catenin入核及核内滞留作用、增加其出核及核外滞留作用,从而阻断Wnt/β-catenin信号通路,也是治疗经典Wnt信号通路相关疾病的有效途径。本文总结近年来关于β-catenin在细胞核内外分布状态的调控机制,为进一步研究治疗经典Wnt信号通路相关疾病提供潜在靶点及新思路。Canonical Wnt signaling pathway plays a crucial role in the proliferation and differentiation of cancer cell. The key protein β-catenin mediates signal transmission from the cytoplasm side to the nucleus side and participates in the formation of transcription complex in the nucleus to activate the transcription of downstream target gene. The entry of β-catenin into the cell nucleus is an important prerequisite for its activation of downstream transcription factors. However,the mechanism of its transportation between nucleus and cytoplasm has not yet been fully understood. The way that β-catenin enters into the nucleus mainly includes utilizing the key proteins of the classical import way to directly enter the nucleus and with the assist of“molecular chaperones”to co-enter the nucleus. While nuclear export of β-catenin mainly relies on the chromosome maintenance region 1(CRM1)-dependent nuclear export. The cadherin on the cell membrane,the degradation complex-related proteins in the cytoplasm,and the transcription complexrelated proteins in the nucleus can all retain β-catenin in the corresponding intracellular area,thereby affecting its cellular sub-localization.Therefore,without changing the total amount of β-catenin in the cell,Wnt/β-catenin signaling pathway can also be blocked by reducing its nuclear import and nuclear retention,or increasing its nuclear export and extranuclear retention,which is also an effective way to treat diseases relevant with this pathway. This review summarizes the mechanism regulating the cellular sub-localization of β-catenin,providing potential targets and new idea for further research on the treatment of canonical Wnt signaling pathway-related diseases.

关 键 词：经典Wnt信号通路 Β-连环蛋白 细胞亚定位 调控机制 治疗靶点 

分 类 号：R73[医药卫生—肿瘤]