Organ size control by Hippo and TOR pathways

The determination of final organ size is a highly coordinated and complex process that relies on the precise regulation of cell number and/or cell size. Perturbation of organ size control contributes to many human diseases, including hypertrophy, degenerative diseases, and cancer. Hippo and TOR are among the key signaling pathways involved in the regulation of organ size through their respective functions in the regulation of cell number and cell size. Here, we review the general mechanisms that regulate organ growth, describe how Hippo and TOR control key aspects of growth, and discuss recent findings that highlight a possible coordination between Hippo and TOR in organ size regulation.     

Coordinating developmental signaling: novel roles for the Hippo pathway

Genetic and biochemical studies have defined the Hippo pathway as a central mediator of developmental and pathogenic signals. By directing intracellular signaling events, the Hippo pathway fine-tunes cell proliferation, cell death, and cell-fate decisions, and coordinates these cues to specify animal organ size. Recent studies have revealed that Hippo pathway-mediated processes are interconnected with those of other key signaling cascades, such as those mediated by TGF-β and Wnt growth factors. Moreover, several reports have described a role for cell contact-mediated polarity proteins in Hippo pathway regulation. Emerging details suggest that crosstalk between these signals drives fundamental developmental processes, and deregulated intercellular communication influences disease progression, such as cancer. We review recent data with a focus on how the Hippo pathway integrates its activity with other signaling pathways.     

The Hippo Pathway Regulates Homeostatic Growth of Stem Cell Niche Precursors in the Drosophila Ovary

The Hippo pathway regulates organ size, stem cell proliferation and tumorigenesis in adult organs. Whether the Hippo pathway influences establishment of stem cell niche size to accommodate changes in organ size, however, has received little attention. Here, we ask whether Hippo signaling influences the number of stem cell niches that are established during development of the Drosophila larval ovary, and whether it interacts with the same or different effector signaling pathways in different cell types. We demonstrate that canonical Hippo signaling regulates autonomous proliferation of the soma, while a novel hippo-independent activity of Yorkie regulates autonomous proliferation of the germ line. Moreover, we demonstrate that Hippo signaling mediates non-autonomous proliferation signals between germ cells and somatic cells, and contributes to maintaining the correct proportion of these niche precursors. Finally, we show that the Hippo pathway interacts with different growth pathways in distinct somatic cell types, and interacts with EGFR and JAK/STAT pathways to regulate non-autonomous proliferation of germ cells. We thus provide evidence for novel roles of the Hippo pathway in establishing the precise balance of soma and germ line, the appropriate number of stem cell niches, and ultimately regulating adult female reproductive capacity.     

Regulation of Hippo signaling pathway in cancer: A MicroRNA perspective

Recent studies have suggested that Hippo signaling is not only involved in controlling organ size in Drosophila but can also regulate cell proliferation, tissue homeostasis, differentiation, apoptosis and regeneration. Any dysregulation of Hippo signaling, especially the hyper activation of its downstream effectors YAP/TAZ, can lead to uncontrolled cell proliferation and malignant transformation. In majority of cancers, expression of YAP/TAZ is extremely high and this increased expression of YAP/TAZ has been shown to be an independent predictor of prognosis and indicator of increased cell proliferation, metastasis and poor survival. In this review, we have summarized the most recent findings about the cross talk of Hippo signaling pathway with other signaling pathways and its regulation by different miRNAs in various cancer types. Recent evidence has suggested that Hippo pathway is also involved in mediating the resistance of different cancer cells to chemotherapeutic drugs and in a few cancer types, this is brought about by regulating miRNAs. Therefore, the delineation of the underlying mechanisms regulating the chemotherapeutic resistance might help in developing better treatment options. This review has attempted to provide an overview of different drugs/options which can be utilized to target oncogenic YAP/TAZ proteins for therapeutic interventions.     

YAP/TAZ对发育和肿瘤的调控及其功能的研究进展

Hippo通路是一种在进化中形成的保守的蛋白激酶级联通路,它与发育中器官的大小和肿瘤的形成有关。Hippo通路的中枢是从肿瘤抑制子Hippo到原癌蛋白YAP/TAZ的激酶级联反应。YAP/TAZ是Hippo通路下游的主要的效应分子,它们广泛表达于多种组织器官中。在哺乳动物细胞中,Hippo通路激酶级联反应通过对YAP/TAZ磷酸化作用,促使其从细胞核转入细胞质中,从而抑制了YAP/TAZ的功能作用。TEAD家族转录子被鉴定为YAP/TAZ发挥生物学功能的重要调节因子。YAP/TAZ的失调引起的相关的基因的表达改变,将会影响细胞的增殖,分化,以及凋亡,从而会影响器官的大小以及肿瘤的形成。本文综述Hippo通路的最新进展,重点关注的是该通路中的YAP/TAZ调控的缺失对发育缺陷和肿瘤的影响。这将为我们研究再生医学,组织工程技术,肿瘤的干预防治提供新的思路与策略。     

YAP1 increases organ size and expands undifferentiated progenitor cells

The mechanisms that regulate mammalian organ size are poorly understood. It is unclear whether the pathways that control organ size also impinge on stem/progenitor cells. A highly expressed gene in stem cells is YAP1, the ortholog of Drosophila Yorkie, a downstream component of the Hippo pathway. Mutations in components of this pathway produce tissue overgrowth phenotypes in the fly whereas mammalian orthologs, like salvador, merlin, LATS, and YAP1, have been implicated in tumorigenesis. We report here that YAP1 increases organ size and causes aberrant tissue expansion in mice. YAP1 activation reversibly increases liver size more than 4-fold. In the intestine, expression of endogenous YAP1 is restricted to the progenitor/stem cell compartment, and activation of YAP1 expands multipotent undifferentiated progenitor cells, which differentiate upon cessation of YAP1 expression. YAP1 stimulates Notch signaling, and administration of gamma-secretase inhibitors suppressed the intestinal dysplasia caused by YAP1. Human colorectal cancers expressing higher levels of YAP1 share molecular aspects with YAP1-induced dysplastic growth in the mouse. Our data show that the Hippo signaling pathway regulates organ size in mammals and can act on stem cell compartments, indicating a potential link between stem/progenitor cells, organ size, and cancer.     

Hippo pathway in intestinal homeostasis and tumorigenesis

The Hippo pathway plays a crucial role in controlling organ size by inhibiting cell proliferation and promoting cell death. Recent findings implicate that this pathway is involved in the process of intestinal regeneration and tumorigenesis. Here we summarize current studies for the function of the Hippo signaling pathway in intestinal homeostasis, regeneration and tumorigenesis, and the crosstalk between the Hippo signaling pathway and other major signaling pathways, i.e. Wnt, Notch and Jak/Stat signaling pathways in intestinal compartment.     

The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway

BACKGROUND: The tight control of cell proliferation and cell death is essential to normal tissue development, and the loss of this control is a hallmark of cancers. Cell growth and cell death are coordinately regulated during development by the Hippo signaling pathway. The Hippo pathway consists of the Ste20 family kinase Hippo, the WW adaptor protein Salvador, and the NDR kinase Warts. Loss of Hippo signaling in Drosophila leads to enhanced cell proliferation and decreased apoptosis, resulting in massive tissue overgrowth through increased expression of targets such as Cyclin E and Diap1. The cytoskeletal proteins Merlin and Expanded colocalize at apical junctions and function redundantly upstream of Hippo. It is not clear how they regulate growth or how they are localized to apical junctions. RESULTS: We find that another Drosophila tumor-suppressor gene, the atypical cadherin fat, regulates both cell proliferation and cell death in developing imaginal discs. Loss of fat leads to increased Cyclin E and Diap1 expression, phenocopying loss of Hippo signaling. Ft can regulate Hippo phosphorylation, a measure of its activation, in tissue culture. Importantly, fat is needed for normal localization of Expanded at apical junctions in vivo. Genetic-epistasis experiments place fat with expanded in the Hippo pathway. CONCLUSIONS: Together, these data suggest that Fat functions as a cell-surface receptor for the Expanded branch of the conserved Hippo growth control pathway.     

Lgl/aPKC and Crb regulate the Salvador/Warts/Hippo pathway

A key goal of developmental biology is to understand the mechanisms that coordinate organ growth. It has long been recognized that the genes that control apico-basal cell polarity also regulate tissue growth. How loss of cell polarity contributes to tissue overgrowth has been the subject of much speculation. Do loss-of-function mutations in cell polarity regulators result in secondary effects that globally deregulate cell proliferation, or do these genes specifically control growth pathways? Three recent papers have shown that the apico-basal polarity determinants Lgl/aPKC and Crb regulate tissue growth independently of their roles in cell polarity and coordinately regulate cell proliferation and cell death via the Salvador/Warts/Hippo (SWH) pathway. Lgl/aPKC are required for the correct localization of Hippo (Hpo)/Ras associated factor (RASSF), while Crb regulates the levels and localization of Expanded (Ex), indicating that cell polarity determinants modify SWH pathway activity by distinct mechanisms. Here, we review the key data that support these conclusions, highlight remaining questions and speculate on the underlying mechanisms by which the cell polarity complexes interact with the SWH pathway. Understanding the interactions between cell polarity regulators and the SWH pathway will improve our knowledge of how epithelial organization and tissue growth are coordinated during development and perturbed in disease states such as cancer.Key words: Drosophila, tumor suppressor gene, cell polarity, Hippo pathway, Crb, Lgl, aPKC     

Regulation of the Hippo pathway by cell architecture and mechanical signals

The Hippo signaling pathway is an evolutionarily conserved mediator of growth control, cell fate decisions and stem cell identity. At the heart of the pathway is a kinase cascade that is reminiscent of other signaling pathways, but recent studies indicate that the Hippo pathway is unique in that it is regulated by cellular architecture and the mechanical properties of the environment. The Hippo pathway may thus serve as a sensor of tissue structure and mechanical tension, integrating information regarding the size and shape of an organ into cellular behavior, such as whether or not to proliferate. In this review we summarize recent discoveries regarding the regulation of the Hippo pathway by cellular polarity, cell junctions, and the cytoskeleton and discuss how these data inform the study of development and disease.     

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.     

Lgl/aPKC and Crb regulate the Salvador/Warts/Hippo pathway

A key goal of developmental biology is to understand the mechanisms that coordinate organ growth. It has long been recognized that the genes that control apico-basal cell polarity also regulate tissue growth. How loss of cell polarity contributes to tissue overgrowth has been the subject of much speculation. Do loss-of-function mutations in cell polarity regulators result in secondary effects that globally deregulate cell proliferation, or do these genes specifically control growth pathways? Three recent papers have shown that the apico-basal polarity determinants Lgl/aPKC and Crb regulate tissue growth independently of their roles in cell polarity and coordinately regulate cell proliferation and cell death via the Salvador/Warts/Hippo (SWH) pathway. Lgl/aPKC are required for the correct localization of Hippo (Hpo)/Ras associated factor (RASSF), whilst Crb regulates the levels and localization of Expanded (Ex), indicating that cell polarity determinants modify SWH pathway activity by distinct mechanisms. Here, we review the key data that support these conclusions, highlight remaining questions and speculate on the underlying mechanisms by which the cell polarity complexes interact with the SWH pathway. Understanding the interactions between cell polarity regulators and the SWH pathway will improve our knowledge of how epithelial organization and tissue growth are coordinated during development and perturbed in disease states such as cancer.     

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。