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。     

Hippo信号调控果蝇中肠稳态维持的机制研究

Hippo信号通路是近年来发现在进化上高度保守的肿瘤抑制信号通路,能通过协调细胞增殖与凋亡来控制组织、器官发育的大小,并在干细胞的自我更新及组织稳态维持中发挥着极其重要的作用。Hippo信号通路关键成员的活性异常可以导致包括癌症在内的多种疾病的发生。因此,Hippo信号通路成员的蛋白稳定性调控是Hippo信号通路研究的重点之一。果蝇中的研究表明,Hippo信号通路上游成员Pez的蛋白稳定性受NEDD4(neural precursor cell expressed developmentally down-regulated protein 4)家族泛素连接酶Su(dx)及Kibra的共同调节,进一步的研究揭示了该调控过程的具体分子机制。该调控在维持果蝇中肠干细胞(intestinal stem cell,ISC)稳态平衡中发挥了重要作用。在哺乳动物细胞中的研究则提示该调控机制存在进化上的保守性。这些研究成果不仅加深了我们对Hippo信号通路调控果蝇肠稳态功能的认识,还为我们研究相关肿瘤发生发展的机制和发掘潜在的肿瘤治疗靶点提供了新的思路。     

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信号通路在果蝇遗传学研究中的发现与扩展

Hippo信号通路的发现是利用果蝇遗传学研究重大生物学问题的又一里程碑式的贡献。大量研究表明,Hippo信号通路像早期发现的其他信号通路一样,也在众多的生理与病理过程中扮演着关键角色,如控制器官尺寸和癌症发生。迄今为止,Hippo信号通路的研究过程主要经历了3个阶段：第一,Hippo信号通路的遗传学发现及其核心因子的筛选与鉴定;第二,Hippo信号通路的调控机制研究;第三,Hippo信号通路的多样性生理学功能。现阶段正是研究Hippo信号通路的上游调控和各种功能的阶段,如细胞骨架、机械张力、营养的调控,功能涉及细胞增殖调控、干细胞生物学和免疫等方面。本文按时间顺序综述了在果蝇遗传学研究中Hippo信号通路的发现与扩展过程,并对未来的研究方向进行了展望。     

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信号通路在乳腺癌中的调控机制及作用

Hippo信号通路是调控器官大小和肿瘤发生发展的关键通路,近年来受到广泛的关注。TAZ/YAP作为哺乳动物中Hippo信号通路两个核心下游效应分子,通过Hippo信号通路依赖性和非依赖性的机制受到细胞内外信号的严密调控。除了参与正常乳腺组织发育,Hippo信号通路还在人乳腺癌细胞的增殖、分化、凋亡、迁移、侵袭、上皮-间质转化和干性维持等多个过程中起着关键性作用。本文总结了Hippo信号通路的调控机制和调节信号,阐述了Hippo信号通路异常在乳腺癌发生发展中的作用,并讨论了其在乳腺癌中作为治疗靶点的临床策略。     

Hippo信号通路生物学作用研究进展

Hippo信号通路是20世纪末在黑腹果蝇中进行基因筛选时发现的,该通路受各种生化、物理和结构信号的影响,调控细胞生长、分化,组织和器官发育以及内环境稳态等基本生物学过程。研究表明Hippo信号通路失调会引起一系列疾病的发生。本文阐述了目前Hippo信号通路在胚胎发育、器官和组织稳态调节、肿瘤的发生发展和细胞自噬等一系列生物学过程以及靶向治疗中的研究进展,其中Hippo信号通路通过细胞自噬来维持机体细胞内环境稳态成为新的研究热点。对该通路的功能和调控机制的深入研究也为组织器官修复再生医学及癌症治疗提供参考。     

Hippo信号通路在雌性生殖系统中的研究进展

Hippo信号通路是一条存在于果蝇属和哺乳动物体内的保守且新兴的信号通路,具有复杂多变的特点。该通路由多种抑癌基因和一种原癌基因组成,与其他信号通路存在诸多交联对话。Hippo信号通路具有调控器官大小、参与调节细胞周期和凋亡及维持内环境稳定等生物学效应。近年来已有研究表明,Hippo信号通路参与雌性生殖系统发育的调控,因此,其在生殖系统发育及疾病治疗中的作用逐渐引起人们的广泛关注。该文综合论述了Hippo信号通路的生理特性及功能,着重阐述其在雌性生殖系统主要生殖器官(如卵巢、乳腺及卵泡等)中的调控机制。     

哺乳动物Hippo信号通路:肿瘤治疗的新标靶

Hippo信号通路是首次在果蝇中发现具有调节细胞增殖与凋亡作用的信号通路。最近发现果蝇Hippo信号通路的组成、分子作用机制和生物学功能在进化过程中高度保守。Hippo信号通路在胚胎发育中对细胞的生长分化、组织器官形成以及成体干细胞的维持和自稳态的保持等方面具有重要作用。同时,Hippo信号通路与Wnt信号通路、Notch信号通路等相互作用、密切联系,在肿瘤的发生、发展过程中也起到关键作用。文章综述了哺乳动物Hippo信号通路的作用机理、与其他信号通路和蛋白质因子的相互联系及与肿瘤的关系,对于肿瘤的诊断、预防和治疗具有一定的参考价值。     

Adhesion Molecule-Mediated Hippo Pathway Modulates Hemangioendothelioma Cell Behavior

Hemangioendotheliomas are categorized as intermediate-grade vascular tumors that are commonly localized in the lungs and livers. The regulation of this tumor cell''s proliferative and apoptotic mechanisms is ill defined. We recently documented an important role for Hippo pathway signaling via endothelial cell adhesion molecules in brain microvascular endothelial cell proliferation and apoptosis. We found that endothelial cells lacking cell adhesion molecules escaped from contact inhibition and exhibited abnormal proliferation and apoptosis. Here we report on the roles of adherens junction molecule modulation of survivin and the Hippo pathway in the proliferation and apoptosis of a murine hemangioendothelioma (EOMA) cell. We demonstrated reduced adherens junction molecule (CD31 and VE-cadherin) expression, increased survivin and Ajuba expression, and a reduction in Hippo pathway signaling resulting in increased proliferation and decreased activation of effector caspase 3 in postconfluent EOMA cell cultures. Furthermore, we confirmed that YM155, an antisurvivin drug that interferes with Sp1-survivin promoter interactions, and survivin small interference RNA (siRNA) transfection elicited induction of VE-cadherin, decreased Ajuba expression, increased Hippo pathway and caspase activation and apoptosis, and decreased cell proliferation. These findings support the importance of the Hippo pathway in hemangioendothelioma cell proliferation and survival and YM155 as a potential therapeutic agent in this category of vascular tumors.     

Hippo signaling in mammalian stem cells

Over the past decade, the Hippo signaling cascade has been linked to organ size regulation in mammals. Indeed, modulation of the Hippo pathway can have potent effects on cellular proliferation and/or apoptosis and a deregulation of the pathway often leads to tumor development. Importantly, emerging evidence indicates that the Hippo pathway can modulate its effects on tissue size by the regulation of stem and progenitor cell activity. This role has recently been associated with the central position of the pathway in sensing spatiotemporal or mechanical cues, and translating them into specific cellular outputs. These results provide an attractive model for how the Hippo cascade might sense and transduce cellular ‘neighborhood’ cues into activation of tissue-specific stem or progenitors cells. A further understanding of this process could allow the development of new therapies for various degenerative diseases and cancers. Here, we review current and emerging data linking Hippo signaling to progenitor cell function.     

The Hippo pathway regulates stem cell proliferation,self-renewal,and differentiation

Stem cells and progenitor cells are the cells of origin for multi-cellular organisms and organs. They play key roles during development and their dysregulation gives rise to human diseases such as cancer. The recent development of induced pluripotent stem cell (iPSC) technology which converts somatic cells to stem-like cells holds great promise for regenerative medicine. Nevertheless, the understanding of proliferation, differentiation, and self-renewal of stem cells and organ-specific progenitor cells is far from clear. Recently, the Hippo pathway was demonstrated to play important roles in these processes. The Hippo pathway is a newly established signaling pathway with critical functions in limiting organ size and suppressing tumorigenesis. This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.     

Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila

Tissue growth is achieved through coordinated cellular growth, cell division and apoptosis. Hippo signaling is critical for monitoring tissue growth during animal development. Loss of Hippo signaling leads to tissue overgrowth due to continuous cell proliferation and block of apoptosis. As cells lacking Hippo signaling are similar in size compared to normal cells, cellular growth must be properly maintained in Hippo signaling-deficient cells. However, it is not clear how Hippo signaling might regulate cellular growth. Here we show that loss of Hippo signaling increased Akt (also called Protein Kinase B, PKB) expression and activity, whereas activation of Hippo signaling reduced Akt expression in developing tissues in Drosophila. While yorkie (yki) is sufficient to increase Akt expression, Akt up-regulation caused by the loss of Hippo signaling is strongly dependent on yki, indicating that Hippo signaling negatively regulates Akt expression through Yki inhibition. Consistently, genetic analysis revealed that Akt plays a critical role in facilitating growth of Hippo signaling-defective tissues. Thus, Hippo signaling not only blocks cell division and promotes apoptosis, but also regulates cellular growth by inhibiting the Akt pathway activity.