科研星球

细胞信号通路详解:Hippo信号通路

      Hippo信号通路是近年来研究的热门方向,最早在果蝇中发现,该信号在不同物种间非常保守,所以在果蝇中通过嵌合遗传筛选获得的Hippo信号通路中的关键分子,都可以在高等动物特别是哺乳动物中,找到相应的直系同源基因。Hippo通路在动物体内参与细胞增殖、凋亡和控制器官大小等重要的生物功能,同时也是肿瘤相关信号通路中最为著名的一条。本文主要介绍Hippo信号通路的主要机制传导方式和近期研究成果。


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Hippo通路机制
The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. 
目前研究已经确定Hippo通路的主要功能是限制组织生长并调节发育中器官中的细胞增殖,分化和迁移。此外,Hippo通路的调节异常会导致异常细胞生长和肿瘤形成。

Hippo signalling pathway controls cell proliferation and survival mainly by sensing the physical state of cells within a tissue through several mechanisms. Unlike other pathways, Hippo does not have dedicated extracellular ligand–receptor complexes. Instead, the upstream signaling of Hippo involves many mechanisms and other signaling pathways. These upstream inputs can be divided into those controlling the pathway by retaining YAP/TAZ in the cytoplasm by physical interaction, and those that activate the core kinase complex MST/LATS leading to YAP/TAZ phosphorylation.
Hippo信号通路主要通过几种机制感知组织内细胞的物理状态来控制细胞增殖和存活。与其他通路不同,Hippo没有专门的细胞外配体-受体复合物。相反,Hippo的上游信号传导涉及许多机制和其他信号传导途径。这些上游输入分为:那些通过物理相互作用将YAP / TAZ保留在细胞质中来控制的通路,以及那些通过激活核心激酶复合物MST / LATS引起YAP / TAZ磷酸化的通路。

The core of Hippo signaling consists of a group of kinases (MST1/2 and LATS1/2) and adaptor proteins SAV1 and MOB1, which by phosphorylating the Hippo pathway effectors YAP and TAZ, retain them in the cytoplasm. In the cytoplasm, YAP/TAZ undergo proteosomal degradation. YAP and TAZ, if not retained in the cytoplasm, can translocate to the nucleus where they regulate the activity of several transcription factors that induce the expression of Hippo target genes involved in cancer development and progression.
Hippo信号传导的核心由一组激酶(MST1 / 2和LATS1 / 2)和衔接蛋白SAV1和MOB1组成,它们通过磷酸化Hippo途径效应分子YAP和TAZ,将它们保留在细胞质中。在细胞质中,YAP / TAZ经历蛋白酶体降解。如果不保留在细胞质中,YAP和TAZ可以易位至细胞核,在那里它们调节几种转录因子的活性,这些转录因子将会诱导参与癌症发展和进展的Hippo靶基因的表达。

Upstream regulation of Hippo includes NF2, KIBRA and WILLIN that activate the core kinase complex. Polarization and adhesion proteins like α-catenin, E-cadherin, CRUMBS, and SCRIBBLE complexes sequester YAP/TAZ in the cytoplasm.
Hippo的上游调节包括激活核心激酶复合物的NF2,KIBRA和WILLIN。极化和粘附蛋白如α-连环蛋白,E-钙粘蛋白,CRUMBS和SCRIBBLE复合物在细胞质中螯合YAP / TAZ。

 GPCRs that can be divided in those signaling through GαS leading to activation of Hippo cascade or those signaling through other Gα subunits that prefer YAP/TAZ nuclear translocation. Mechanical stress regulated by F-actin can also increase YAP/TAZ cytoplasmic location. In addition, independent proteins like Rassf1a and several pathways regulate Hippo signaling.
该通路的G蛋白偶联受体(GPCRs)可以分为:(1)通过GαS信号传导导致Hippo级联激活的GPCR; (2)通过其他更喜欢YAP / TAZ核易位的Gα亚基信号传导的GPCR。同时有研究表明由F-肌动蛋白调节的机械应力也可以增加YAP / TAZ细胞质位置。此外,像Rassf1a和几种途径的独立蛋白质调节Hippo信号传导。

Hippo通路近期研究 
近年来的研究发现Hippo信号传导通路在癌症发生和转移、组织再生以及免疫调控上发挥着重要的作用。比如:
(1)研究人员发现Hippo通路可以组织心肌再生,所以可以通过沉默Hippo活性来逆转重度心力衰竭,该研究工作发表在Nature上,给心脏病治疗带来了新的机遇。
(2)Oncegene上发表的研究阐明Hippo通路关键转录因子TEAD4特异性结合DNA分子机制,揭示了该通路在胃肠道恶性肿瘤及免疫应答中的机制与功能,给多个新疾病诊疗提供了标识物和药物靶标。
(3)近年有研究揭示了Hippo通路中的原癌蛋白YAP2新的分子调控机制,该蛋白的翻译后乙酰化和去乙酰化修饰可增强与转录因子TEAD4的结合。研究人员发现在抗肿瘤药物(CDDP)处理下可增强肝癌细胞的增殖和对抗肿瘤药物的抵抗。这个研究将为肝癌的治疗提供新的依据。
(4)有PLoS ONE文献已经证明c-Abl-Hippo/MST2通路调节了神经元细胞的死亡,哺乳动物MSTs是果蝇Hippo的同源物,在调节细胞死亡,控制器官大小及肿瘤发生有至关重要的作用。
Hippo信号的研究有利于今后人类多种癌症、组织再生等的治疗,提高肿瘤治疗的特异性和靶向性,减少药物对正常干细胞的损伤以及在癌症中的耐药机制。


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