Hippo信号通路调控免疫细胞的功能

Hippo信号通路最初是在果蝇(Drosophila)中被发现的,是在进化上高度保守并能调控器官大小的信号转导通路。在哺乳动物多种组织器官中,Hippo信号通路的关键激酶MST1和MST2(果蝇Hippo激酶的同源分子)通过抑制下游的转录共激活分子YAP(果蝇中为Yorki)的活性来实现对细胞增殖和凋亡的调控。在这些组织器官中条件性敲除Mst1和Mst2或过表达Yap大都会造成细胞过度增殖或肿瘤的发生。近年来,随着研究的不断深入,Hippo信号通路不依赖于YAP的非经典功能也逐渐被发现。其中,Hippo信号通路多个成员在免疫系统中的调控功能逐渐成为该领域的研究热点,特别是在免疫细胞发育分化、机体自身免疫性疾病及应对病毒和细菌入侵等过程中所发挥的调控作用。本文重点阐述了Hippo信号通路在T淋巴细胞中发育、分化、活化和迁移等方面及在部分天然免疫细胞抗感染过程中的功能和调控。     

Hippo通路在神经发育和神经系统疾病中的功能

Hippo通路是一个调控组织器官大小、细胞增殖、分化和凋亡的高度保守的信号通路.我们研究了氧化压力条件下Hippo通路在神经细胞中的作用,并发现哺乳动物STE20样的丝-苏氨酸蛋白激酶(MST1)可参与氧化应激诱导的神经细胞凋亡,其上游受非受体酪氨酸激酶c-Abl的调控.近期,我们研究发现MST1参与脑缺血引起的神经炎症,还发现Yes相关蛋白1(YAP)参与神经干细胞的自我更新.本文将介绍Hippo通路在中枢神经系统疾病和神经发育中的作用和机制研究的相关进展.     

综述: Hippo通路在神经发育和神经系统疾病中的功能

Hippo通路是一个调控组织器官大小、细胞增殖、分化和凋亡的高度保守的信号通路.我们研究了氧化压力条件下Hippo通路在神经细胞中的作用,并发现哺乳动物STE20样的丝-苏氨酸蛋白激酶(MST1)可参与氧化应激诱导的神经细胞凋亡,其上游受非受体酪氨酸激酶c-Abl的调控.近期,我们研究发现MST1参与脑缺血引起的神经炎症,还发现Yes相关蛋白1(YAP)参与神经干细胞的自我更新.本文将介绍Hippo通路在中枢神经系统疾病和神经发育中的作用和机制研究的相关进展.     

Hippo-YAP/TAZ与Notch信号通路在肝纤维化中的作用

病毒性或代谢性慢性肝病引起的肝纤维化是全球健康的一大挑战。Hippo-YAP/TAZ通路与Notch信号通路在肝纤维化进展中发挥了至关重要的作用。经典的Hippo通路核心激酶级联在大量外界信号的作用下，通过磷酸化使转录共激活因子YAP/TAZ失活，从而调控细胞的生长与增殖以及干细胞再生、肿瘤形成等过程。Notch信号通路通过调控脂质代谢、IR、氧化应激、自噬、炎症与纤维化等方面参与肝病的发生与发展。该文就Hippo-YAP/TAZ与Notch信号通路在肝纤维化过程中对肝星状细胞、巨噬细胞、肝脂质代谢等方面的影响及两条通路的交互作用进行了详细地综述。概括了2条通路在肝纤维化中的研究现状，总结分析了交互作用研究中存在的问题和未来的方向，旨在为肝纤维化的防治提供新的靶点和理论依据。     

Hippo信号通路与肝脏稳态调控及疾病发生

肝脏是人体最重要的器官之一,乙肝等病毒性与酒精等非病毒性因素诱发的肝损伤引起肝脏功能衰竭、再生重塑障碍、肝癌等疾病是我国重大社会健康问题,因此,研究肝脏稳态的调控机制对肝病的预防和临床治疗至关重要。Hippo信号通路参与了哺乳动物多种细胞和器官的稳态调控。最近研究表明,Hippo信号通路在肝脏发育、肝细胞命运决定、肝脏再生和癌症发生发展等过程中都发挥了非常重要的作用。因此,Hippo信号通路可成为肝脏相关疾病的治疗提供了新的靶点。本文综述了Hippo信号通路与肝脏稳态调控的相关研究及最新进展,以期为研究肝脏发育和肝脏相关疾病的治疗提供新的思路和策略。     

Hippo信号通路在肺发育、再生和疾病中的功能

哺乳动物肺对于血液与外部环境之间的气体交换至关重要。而肺相关的疾病是现代人死亡的主要原因之一。肺的发育、再生和相关疾病的研究对临床治疗具有重要的指导作用。研究发现,Hippo信号通路参与细胞增殖与分化的调控、器官大小的控制,以及机械力的感应和传递。Hippo信号通路中的核心转录调控分子YAP/TAZ在肺部的多种细胞中均有表达,其表达及定位的变化在肺发育与再生中发挥着重要的调控作用。本文主要介绍了Hippo信号通路在肺生长发育中的功能及其与肺纤维化、肺癌的关系,并从肺泡力学和肺泡相关免疫两个角度对Hippo信号通路潜在的功能进行了展望。     

Hippo信号通路相关分子参与免疫细胞功能调控的研究进展

Hippo信号通路是最早在果蝇(Drosophila)中发现的,在进化上高度保守,具有调控细胞增殖与凋亡作用的一条关键信号转导通路。在哺乳动物中,Hippo信号通路在调控细胞增殖、细胞死亡、细胞分化和肿瘤生成等生物学过程中有着十分重要的作用。近年来,Hippo信号通路在免疫系统以及多种功能性免疫细胞中发挥的重要作用逐渐成为该领域的研究热点,特别是Hippo信号通路各成员在免疫细胞应对病毒、细菌入侵或肿瘤发生以及维持自身稳态过程中发挥着重要的作用。因此,深入了解Hippo信号通路各成员对多种功能性免疫细胞的调控机制,有助于绘制新的免疫系统调控网络,阐明各类免疫系统相关疾病的发病机制,期望为诊断、治疗和预防相关疾病提供新的治疗策略或靶点。     

Hippo信号通路结构生物学研究进展

生物体内存在多种信号转导通路参与发育调控和组织稳态维持等重要过程,其信号异常与多种疾病特别是癌症的发生和发展密切相关。进化上高度保守的Hippo信号通路在个体发育和稳态平衡中发挥极为关键的作用。Hippo信号通路主要通过一系列相关激酶的相互作用和级联磷酸化来传递信号,能抑制细胞增殖并促进凋亡,在很多组织器官中控制细胞数量和器官大小。Hippo信号通路在一系列恶性肿瘤中出现显著异常,被认为是癌症治疗和再生医学的重要靶标。目前,Hippo信号通路中大部分关键组分已经确定,而其具体信号调控机制及功能正在完善之中。本文总结了目前已知的Hippo信号通路各蛋白成员的结构信息,重点从结构生物学角度对其信号的转导与调控机制进行分析,并对已有的Hippo信号通路靶向小分子及多肽抑制剂进行梳理,以期深化人们对该通路关键蛋白质机器的理解,并进一步促进相关的功能研究和潜在的治疗干预研发。     

Mst1 and Mst2 kinases: regulations and diseases

The Hippo signaling pathway has emerged as a critical regulator for organ size control. The serine/threonine protein kinases Mst1 and Mst2, mammalian homologs of the Hippo kinase from Drosophila, play the central roles in the Hippo pathway controlling the cell proliferation, differentiation, and apoptosis during development. Mst1/2 can be activated by cellular stressors and the activation of Mst1/2 might enforce a feedback stimulation system to regulate oxidant levels through several mechanisms, in which regulation of cellular redox state might represent a tumor suppressor function of Mst1/2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in multiple organs, although considerable diversification in the pathway composition and regulation is observed in some of them. Generally, loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by the reduction or elimination of YAP. The Hippo pathway integrates with other signaling pathways e.g. Wnt and Notch pathways and coordinates with them to impact on the tumor pathogenesis and development. Furthermore, Mst1/2 kinases also act as an important regulator in immune cell activation, adhesion, migration, growth, and apoptosis. This review will focus on the recent updates on those aspects for the roles of Mst1/2 kinases.     

Taming the Hippo: Raf-1 Controls Apoptosis by Suppressing MST2/Hippo

The Raf-1 kinase has a well established role in activating the MEK-ERK/MAPK pathway.However, accumulating evidence including the phenotype of Raf-1-/- mice suggested thatRaf-1 may have other functions independent of its role as MEK activator, in particularpertaining to protection against apoptosis. We have recently demonstrated a new role of Raf-1 by showing that Raf-1 controls the proapoptotic kinase MST2/Hippo. In mammalian cellsMST2 is activated by stress signals and causes apoptosis when overexpressed. Its Drosophilahomologue Hippo regulates apoptosis and cell cycle arrest during differentiation. Raf-1inhibits MST2 by preventing its dimerisation and recruiting a phosphatase that removesactivating phosphorylations on MST2. Both functions require Raf-1 binding to MST2, butare independent of Raf-1’s kinase activity and the ERK pathway. Downregulation of MST2by siRNA reverts the apoptosis hypersensitivity of Raf-1-/- mouse fibroblasts. In contrast, thedownregulation of Raf-1 in Raf-1+/+ cells and human cancer cell lines enhances susceptibilityto Fas induced apoptosis, which is rescued by concomitant downregulation of both Raf-1 andMST2. The MST2:Raf-1 complex is dissociated by stress signals as well as mitogens. Stresssignals robustly activate MST2 and trigger apoptosis. Mitogens only make MST2 permissivefor activation by releasing it from Raf-1, and in addition activate survival pathways allowingproliferation. Thus, by linking mitogenic and apoptotic signalling the MST:Raf-1 complexmay serve as a safeguard against unlicensed proliferation.     

Melatonin attenuates inflammation-related venous endothelial cells apoptosis through modulating the MST1–MIEF1 pathway

Chronic venous disease (CVD) is a prevalent and potentially debilitating condition that affects millions of individuals. An excessive endothelial inflammatory response is reportedly involved in the development of CVD. In this study, we explored the effect and mechanism of melatonin on venous endothelial damage induced by tumor necrosis factor α (TNF-α). Our data demonstrated that inflammation injury triggered mitochondrial dysfunction, activated reactive oxygen species-related oxidative damage, inhibited mitochondrial potential and ultimately initiated caspase-involved cellular death. Interestingly, melatonin preserved inflammation-attacked mitochondrial performance and thus increased cell survival under TNF-α. Cellular experiments illustrated that inflammation injury promoted the levels of mammalian sterile 20-like kinase 1 (MST1) and mitochondrial elongation factor 1 (MIEF1); active MST1–MIEF1 pathway disturbed mitochondria-related energy production, leading to mitochondria-induced cell damage. Interestingly, melatonin effectively suppressed MST1–MIEF1 axis and thus improved cell survival ratio under TNF-α-mediated inflammation injury. Reactivation of MST1–MIEF1 pathway attenuated melatonin-related endothelial protective actions. Herein, our results illuminate that melatonin is an effective approach to attenuate inflammation-related venous endothelial cell damage through handling the MST1–MIEF1 signaling pathway.     

Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway

Recent studies have shown that the Hippo-Salvador-Warts (HSW) pathway restrains tissue growth by phosphorylating and inactivating the oncoprotein Yorkie. How growth-suppressive signals are transduced upstream of Hippo remains unclear. We show that the Sterile 20 family kinase, Tao-1, directly phosphorylates T195 in the Hippo activation loop and that, like other HSW pathway genes, Tao-1 functions to restrict cell proliferation in developing imaginal epithelia. This relationship appears to be evolutionarily conserved, because mammalian Tao-1 similarly affects MST kinases. In S2 cells, Tao-1 mediates the effects of the upstream HSW components Merlin and Expanded, consistent with the idea that Tao-1 functions in tissues to regulate Hippo phosphorylation. These results demonstrate that one family of Ste20 kinases can activate another and identify Tao-1 as a component of the regulatory network controlling HSW pathway signaling, and therefore tissue growth, during development.