scholarly journals The Hippo pathway coactivator Yorkie can reprogram cell fates and create compartment-boundary–like interactions at clone margins

2020 ◽  
Vol 6 (50) ◽  
pp. eabe8159
Author(s):  
Joanna C. D. Bairzin ◽  
Maya Emmons-Bell ◽  
Iswar K. Hariharan
Keyword(s):  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Activity Levels ◽  
Cell Fates ◽  
Cubitus Interruptus ◽  
Compartment Boundary ◽  
Pathway Activation ◽  
Chromatin Regulator ◽  
Heterotypic Interactions ◽  
The Hippo Pathway

During development, tissue-specific patterns of gene expression are established by transcription factors and then stably maintained via epigenetic mechanisms. Cancer cells often express genes that are inappropriate for that tissue or developmental stage. Here, we show that high activity levels of Yki, the Hippo pathway coactivator that causes overgrowth in Drosophila imaginal discs, can also disrupt cell fates by altering expression of selector genes like engrailed (en) and Ultrabithorax (Ubx). Posterior clones expressing activated Yki can down-regulate en and express an anterior selector gene, cubitus interruptus (ci). The microRNA bantam and the chromatin regulator Taranis both function downstream of Yki in promoting ci expression. The boundary between Yki-expressing posterior clones and surrounding wild-type cells acquires properties reminiscent of the anteroposterior compartment boundary; Hedgehog signaling pathway activation results in production of Dpp. Thus, at least in principle, heterotypic interactions between Yki-expressing cells and their neighbors could activate boundary-specific signaling mechanisms.

scholarly journals Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

2020 ◽  
Author(s):  
Sherzod A. Tokamov ◽  
Ting Su ◽  
Anne Ullyot ◽  
Richard G. Fehon
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
The Core ◽  
Pathway Activation ◽  
The Hippo Pathway ◽  
Transcriptional Output

AbstractThe Hippo signaling pathway regulates tissue growth in many animals. Multiple upstream components are known to promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Kibra levels independently of Yorkie-mediated transcriptional output. We find that the Hippo pathway promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires the core kinases Hippo and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators including Crumbs and Expanded. Moreover, Kibra degradation appears patterned across tissue. We propose that Kibra degradation by the Hippo pathway serves as a negative feedback loop to tightly control Kibra-mediated Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

scholarly journals Localized JNK signaling regulates organ size during development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Helen Rankin Willsey ◽  
Xiaoyan Zheng ◽  
José Carlos Pastor-Pareja ◽  
A Jeremy Willsey ◽  
Philip A Beachy ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Size Control ◽  
Organ Size ◽  
Control Mechanisms ◽  
Cancer Therapies ◽  
Independent Manner ◽  
Jnk Signaling ◽  
New Strategy ◽  
The Hippo Pathway

A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control.

scholarly journals Liver Zonation in Health and Disease: Hypoxia and Hypoxia-Inducible Transcription Factors as Concert Masters

2019 ◽  
Vol 20 (9) ◽  
pp. 2347 ◽  
Author(s):  
Thomas Kietzmann
Keyword(s):  
Transcription Factors ◽  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Cell Types ◽  
Whole Body ◽  
Liver Zonation ◽  
Current Review ◽  
Health And Disease ◽  
The Hippo Pathway ◽  
Dynamic Interplay

The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis.

scholarly journals Regulation and functions of the Hippo pathway in stemness and differentiation

2020 ◽  
Vol 52 (7) ◽  
pp. 736-748 ◽  
Author(s):  
Xiaolei Cao ◽  
Chenliang Wang ◽  
Jiyang Liu ◽  
Bin Zhao
Keyword(s):  
Cell Proliferation ◽  
Tissue Regeneration ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Cell Fates ◽  
Self Renewal ◽  
Proliferation And Apoptosis ◽  
Kinase Cascade ◽  
The Hippo Pathway

Abstract The Hippo pathway plays important roles in organ development, tissue regeneration, and human diseases, such as cancer. In the canonical Hippo pathway, the MST1/2-LATS1/2 kinase cascade phosphorylates and inhibits transcription coactivators Yes-associated protein and transcription coactivator with PDZ-binding motif and thus regulates transcription of genes important for cell proliferation and apoptosis. However, recent studies have depicted a much more complicate picture of the Hippo pathway with many new components and regulatory stimuli involving both chemical and mechanical signals. Furthermore, accumulating evidence indicates that the Hippo pathway also plays important roles in the determination of cell fates, such as self-renewal and differentiation. Here, we review regulations of the Hippo pathway and its functions in stemness and differentiation emphasizing recent discoveries.

Patterning of Drosophila leg sensory organs through combinatorial signaling by hedgehog, decapentaplegic and wingless

Development ◽  
1999 ◽  
Vol 126 (13) ◽  
pp. 2891-2899 ◽  
Author(s):  
R. Hays ◽  
K.T. Buchanan ◽  
C. Neff ◽  
T.V. Orenic
Keyword(s):  
Cell Fate ◽  
Imaginal Disc ◽  
Sensory Cell ◽  
Individual Cell ◽  
Cell Types ◽  
Cell Fates ◽  
Cubitus Interruptus ◽  
Compartment Boundary ◽  
Local Environments ◽  
Ectopic Activation

During development, global patterning events initiate signal transduction cascades which gradually establish an array of individual cell fates. Many of the genes which pattern Drosophila are expressed throughout development and specify diverse cell types by creating unique local environments which establish the expression of locally acting genes. This process is exemplified by the patterning of leg microchaete rows. hairy (h) is expressed in a spatially restricted manner in the leg imaginal disc and functions to position adult leg bristle rows by negatively regulating the proneural gene achaete, which specifies sensory cell fates. While much is known about the events that partition the leg imaginal disc and about sensory cell differentiation, the mechanisms that refine early patterning events to the level of individual cell fate specification are not well understood. We have investigated the regulation of h expression along the dorsal/ventral (D/V) axis of the leg adjacent to the anterior/posterior (A/P) compartment boundary and have found that it requires input from both D/V and A/P patterning mechanisms. Expression of the D/V axis h stripe (D/V-h) is controlled by dorsal- and ventral-specific enhancer elements which are targets of Decapentaplegic (Dpp) and Wingless (Wg) signaling, respectively, but which are also dependent on Hedgehog (Hh) signaling for activation. D/V-h expression is lost in smoothened mutant clones and is specifically activated by exogenously supplied Cubitus interruptus (Ci). D/V-h expression is also lost in clones deficient for Dpp and Wg signaling, but ectopic activation of D/V-h by Dpp and Wg is limited to the A/P compartment boundary where endogenous levels of full-length Ci are high. We propose that D/V-h expression is regulated in a non-linear pathway in which Ci plays a dual role. In addition to serving as an upstream activator of Dpp and Wg, Ci acts combinatorially with them to activate D/V-h expression.

scholarly journals The Hippo pathway acts downstream of the Hedgehog signaling to regulate follicle stem cell maintenance in the Drosophila ovary

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Ta-Hsing Hsu ◽  
Chia-Yu Yang ◽  
Tsung-Han Yeh ◽  
Yi-Chia Huang ◽  
Tsu-Wei Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hedgehog Signaling ◽  
Hippo Pathway ◽  
Stem Cell Maintenance ◽  
The Hippo Pathway ◽  
Drosophila Ovary ◽  
Cell Maintenance

scholarly journals Hippo Pathway in Regulating Drug Resistance of Glioblastoma

2021 ◽  
Vol 22 (24) ◽  
pp. 13431
Author(s):  
Giacomo Casati ◽  
Laura Giunti ◽  
Anna Lisa Iorio ◽  
Arianna Marturano ◽  
Luisa Galli ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Pathway Activation ◽  
Promising Target ◽  
Kinase Cascade ◽  
Tumor Immunosuppression ◽  
The Central Nervous System ◽  
Immunosuppressive Microenvironment ◽  
The Hippo Pathway

Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.

scholarly journals Resveratrol Inhibits Hepatic Stellate Cell Activation via the Hippo Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Chunxue Li ◽  
Rongrong Zhang ◽  
Yating Zhan ◽  
Jianjian Zheng
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Hepatitis Virus ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Virus Infections ◽  
Pathway Activation ◽  
The Hippo Pathway

Liver fibrosis, which results from chronic liver injury due to factors such as chronic alcohol consumption, hepatitis virus infections, and immune attacks, is marked by excessive deposition of extracellular matrix (ECM). Resveratrol (Res), a polyphenol phytoalexin, has been demonstrated to show anti-inflammatory, antioxidative, antiproliferative, and chemopreventive activities. In recent years, Res has been found to inhibit liver fibrosis. Enhanced Hippo pathway activation has also been reported to inhibit tumor progression and liver fibrosis. In the present study, the role of the Hippo pathway in mediating the effects of Res on hepatic stellate cells (HSCs) was examined. We found that Res significantly suppresses HSC proliferation, reducing the cell index. Res induced HSC inactivation, reducing collagen deposition and α-smooth muscle actin (α-SMA) expression. In addition, Res contributed to HSC apoptosis, upregulating Bax and downregulating Bcl-2 expression. Notably, the Hippo pathway was involved in the Res-mediated suppression of HSC activation. Res enhanced the activation of the Hippo pathway and reduced yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) expression. Interestingly, the YAP overexpression inhibited Res-induced HSC inactivation and apoptosis. In conclusion, these results demonstrate that Res inhibits HSC activation, at least in part, via the Hippo pathway. The present study indicates a new antifibrotic mechanism of Res and provides novel insights into Hippo-mediated HSC apoptosis and HSC activation in liver fibrosis.

scholarly journals The ZO-1 protein Polychaetoid as an upstream regulator of the Hippo pathway in Drosophila

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009894
Author(s):  
Qingliang Sang ◽  
Gang Wang ◽  
David B. Morton ◽  
Hui Wu ◽  
Baotong Xie
Keyword(s):  
Hippo Pathway ◽  
Hippo Signaling ◽  
Fate Specification ◽  
Upstream Regulator ◽  
Neuronal Fate ◽  
Zonula Occludens ◽  
Pathway Activation ◽  
Core Components ◽  
The Hippo Pathway ◽  
Neuronal Fate Specification

The generation of a diversity of photoreceptor (PR) subtypes with different spectral sensitivities is essential for color vision in animals. In the Drosophila eye, the Hippo pathway has been implicated in blue- and green-sensitive PR subtype fate specification. Specifically, Hippo pathway activation promotes green-sensitive PR fate at the expense of blue-sensitive PRs. Here, using a sensitized triple heterozygote-based genetic screening approach, we report the identification of the single Drosophila zonula occludens-1 (ZO-1) protein Polychaetoid (Pyd) as a new regulator of the Hippo pathway during the blue- and green-sensitive PR subtype binary fate choice. We demonstrate that Pyd acts upstream of the core components and the upstream regulator Pez in the Hippo pathway. Furthermore, We found that Pyd represses the activity of Su(dx), a E3 ligase that negatively regulates Pez and can physically interact with Pyd, during PR subtype fate specification. Together, our results identify a new mechanism underlying the Hippo signaling pathway in post-mitotic neuronal fate specification.

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