scholarly journals Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

2007 ◽  
Vol 21 (21) ◽  
pp. 2747-2761 ◽  
Author(s):  
B. Zhao ◽  
X. Wei ◽  
W. Li ◽  
R. S. Udan ◽  
Q. Yang ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Contact Inhibition ◽  
Cell Contact ◽  
The Hippo Pathway

scholarly journals The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat

2016 ◽  
Vol 216 (1) ◽  
pp. 265-277 ◽  
Author(s):  
Hitoshi Matakatsu ◽  
Seth S. Blair ◽  
Richard G. Fehon
Keyword(s):  
Posttranslational Modification ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Negative Regulator ◽  
Pathway Activity ◽  
Protein Association ◽  
Junctional Region ◽  
Growth Loss ◽  
The Hippo Pathway

The large protocadherin Fat functions to promote Hippo pathway activity in restricting tissue growth. Loss of Fat leads to accumulation of the atypical myosin Dachs at the apical junctional region, which in turn promotes growth by inhibiting Warts. We previously identified Approximated (App), a DHHC domain palmitoyltransferase, as a negative regulator of Fat signaling in growth control. We show here that App promotes growth by palmitoylating the intracellular domain of Fat, and that palmitoylation negatively regulates Fat function. Independently, App also recruits Dachs to the apical junctional region through protein–protein association, thereby stimulating Dachs’s activity in promoting growth. Further, we show that palmitoylation by App functions antagonistically to phosphorylation by Discs-overgrown, which activates Fat. Together, these findings suggest a model in which App promotes Dachs activity by simultaneously repressing Fat via posttranslational modification and recruiting Dachs to the apical junctional region, thereby promoting tissue growth.

scholarly journals Genome-Wide Screen for Context-Dependent Tumor Suppressors Identified Using in Vivo Models for Neoplasia in Drosophila

2020 ◽  
Vol 10 (9) ◽  
pp. 2999-3008 ◽  
Author(s):  
Casper Groth ◽  
Pooja Vaid ◽  
Aditi Khatpe ◽  
Nelchi Prashali ◽  
Avantika Ahiya ◽  
...  
Keyword(s):  
Large Scale ◽  
Hippo Pathway ◽  
Growth Control ◽  
Growth Factor Receptor ◽  
Tissue Growth ◽  
In Vivo Models ◽  
Genome Wide ◽  
Positive Regulators ◽  
The Hippo Pathway

Abstract Genetic approaches in Drosophila have successfully identified many genes involved in regulation of growth control as well as genetic interactions relevant to the initiation and progression of cancer in vivo. Here, we report on large-scale RNAi-based screens to identify potential tumor suppressor genes that interact with known cancer-drivers: the Epidermal Growth Factor Receptor and the Hippo pathway transcriptional cofactor Yorkie. These screens were designed to identify genes whose depletion drove tissue expressing EGFR or Yki from a state of benign overgrowth into neoplastic transformation in vivo. We also report on an independent screen aimed to identify genes whose depletion suppressed formation of neoplastic tumors in an existing EGFR-dependent neoplasia model. Many of the positives identified here are known to be functional in growth control pathways. We also find a number of novel connections to Yki and EGFR driven tissue growth, mostly unique to one of the two. Thus, resources provided here would be useful to all researchers who study negative regulators of growth during development and cancer in the context of activated EGFR and/or Yki and positive regulators of growth in the context of activated EGFR. Resources reported here are available freely for anyone to use.

scholarly journals The Hippo Pathway: Biology and Pathophysiology

2019 ◽  
Vol 88 (1) ◽  
pp. 577-604 ◽  
Author(s):  
Shenghong Ma ◽  
Zhipeng Meng ◽  
Rui Chen ◽  
Kun-Liang Guan
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Tissue Growth ◽  
Cell Contact ◽  
Energy Status ◽  
Downstream Effectors ◽  
Kinase Cascade ◽  
Fate Decision ◽  
The Hippo Pathway

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell–cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein–coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.

scholarly journals The miRNA bantam regulates growth and tumorigenesis by repressing the cell cycle regulator tribbles

2019 ◽  
Vol 2 (4) ◽  
pp. e201900381 ◽  
Author(s):  
Stephan U Gerlach ◽  
Moritz Sander ◽  
Shilin Song ◽  
Héctor Herranz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Tumor Formation ◽  
Hippo Signaling ◽  
Cell Cycle Regulators ◽  
The Hippo Pathway

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

scholarly journals Amotl2a interacts with the Hippo effector Yap1 and the Wnt/β-catenin effector Lef1 to control tissue size in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sobhika Agarwala ◽  
Sandra Duquesne ◽  
Kun Liu ◽  
Anton Boehm ◽  
Lin Grimm ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Cell Junction ◽  
Hippo Signaling ◽  
Sensory Organs ◽  
Hippo Signaling Pathway ◽  
Tissue Size ◽  
The Hippo Pathway ◽  
First Time

During development, proliferation must be tightly controlled for organs to reach their appropriate size. While the Hippo signaling pathway plays a major role in organ growth control, how it senses and responds to increased cell density is still unclear. In this study, we use the zebrafish lateral line primordium (LLP), a group of migrating epithelial cells that form sensory organs, to understand how tissue growth is controlled during organ formation. Loss of the cell junction-associated Motin protein Amotl2a leads to overproliferation and bigger LLP, affecting the final pattern of sensory organs. Amotl2a function in the LLP is mediated together by the Hippo pathway effector Yap1 and the Wnt/β-catenin effector Lef1. Our results implicate for the first time the Hippo pathway in size regulation in the LL system. We further provide evidence that the Hippo/Motin interaction is essential to limit tissue size during development.

scholarly journals Genome-wide RNAi screen for context-dependent tumor suppressors identified using in vivo models for neoplasia in Drosophila

2019 ◽  
Author(s):  
Casper Groth ◽  
Pooja Vaid ◽  
Aditi Khatpe ◽  
Nelchi Prashali ◽  
Avantika Ahiya ◽  
...  
Keyword(s):  
Large Scale ◽  
Hippo Pathway ◽  
Growth Control ◽  
Growth Factor Receptor ◽  
Tissue Growth ◽  
In Vivo Models ◽  
Genome Wide ◽  
Positive Regulators ◽  
The Hippo Pathway

AbstractGenetic approaches in Drosophila have successfully identified many genes involved in regulation of growth control as well as genetic interactions relevant to the initiation and progression of cancer in vivo. Here, we report on large-scale RNAi-based screens to identify potential tumor suppressor genes that interact with known cancer-drivers: The Epidermal Growth Factor Receptor and the Hippo pathway transcriptional cofactor Yorkie. These screens were designed to identify genes whose depletion drove tissue expressing EGFR or Yki from a state of benign overgrowth into neoplastic transformation in vivo. We also report on an independent screen aimed to identify genes whose depletion suppressed formation of neoplastic tumors in an existing EGFR-dependent neoplasia model. Many of the positives identified here are known to be functional in growth control pathways. We also find a number of novel connections to Yki and EGFR driven tissue growth, mostly unique to one of the two. Thus, resources provided here would be useful to all researchers who study negative regulators of growth in the context of activated EGFR and/or Yki and positive regulators of growth in the context of activated EGFR.

scholarly journals Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 611
Author(s):  
Kelly Coffey
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Hippo Pathway ◽  
Effector Proteins ◽  
Migration And Invasion ◽  
Cell Contact ◽  
Cellular Localisation ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
Emergence Of Resistance

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

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