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 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 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 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 NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

Drosophila Hcf regulates the Hippo signaling pathway via association with the histone H3K4 methyltransferase Trr

2019 ◽  
Vol 476 (4) ◽  
pp. 759-768 ◽  
Author(s):  
Zi Nan ◽  
Weiwei Yang ◽  
Jialan Lyu ◽  
Fang Wang ◽  
Qiannan Deng ◽  
...  
Keyword(s):  
Host Cell ◽  
Signaling Pathway ◽  
Hippo Pathway ◽  
Organ Size ◽  
Fundamental Aspect ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Host Cell Factor ◽  
Histone H3k4 ◽  
The Hippo Pathway

Abstract Control of organ size is a fundamental aspect in biology and plays important roles in development. The Hippo pathway is a conserved signaling cascade that controls tissue and organ size through the regulation of cell proliferation and apoptosis. Here, we report on the roles of Hcf (host cell factor), the Drosophila homolog of Host cell factor 1, in regulating the Hippo signaling pathway. Loss-of-Hcf function causes tissue undergrowth and the down-regulation of Hippo target gene expression. Genetic analysis reveals that Hcf is required for Hippo pathway-mediated overgrowth. Mechanistically, we show that Hcf associates with the histone H3 lysine-4 methyltransferase Trithorax-related (Trr) to maintain H3K4 mono- and trimethylation. Thus, we conclude that Hcf positively regulates Hippo pathway activity through forming a complex with Trr and controlling H3K4 methylation.

scholarly journals A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

2020 ◽  
Vol 26 (9) ◽  
pp. 653-664
Author(s):  
Challis Karasek ◽  
Mohamed Ashry ◽  
Chad S Driscoll ◽  
Jason G Knott
Keyword(s):  
Signaling Pathway ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Cell Mass ◽  
Preimplantation Embryos ◽  
Hippo Signaling ◽  
Cell Fate Decisions ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway

Abstract In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.

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 Interaction of the Hippo Pathway and Phosphatases in Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2438 ◽  
Author(s):  
Sahar Sarmasti Emami ◽  
Derek Zhang ◽  
Xiaolong Yang
Keyword(s):  
Signaling Pathway ◽  
Hippo Pathway ◽  
Underlying Mechanism ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Cellular Processes ◽  
Wide Range ◽  
Future Direction ◽  
The Hippo Pathway

The Hippo pathway is an emerging tumor suppressor signaling pathway involved in a wide range of cellular processes. Dysregulation of different components of the Hippo signaling pathway is associated with a number of diseases including cancer. Therefore, identification of the Hippo pathway regulators and the underlying mechanism of its regulation may be useful to uncover new therapeutics for cancer therapy. The Hippo signaling pathway includes a set of kinases that phosphorylate different proteins in order to phosphorylate and inactivate its main downstream effectors, YAP and TAZ. Thus, modulating phosphorylation and dephosphorylation of the Hippo components by kinases and phosphatases play critical roles in the regulation of the signaling pathway. While information regarding kinase regulation of the Hippo pathway is abundant, the role of phosphatases in regulating this pathway is just beginning to be understood. In this review, we summarize the most recent reports on the interaction of phosphatases and the Hippo pathway in tumorigenesis. We have also introduced challenges in clarifying the role of phosphatases in the Hippo pathway and future direction of crosstalk between phosphatases and the Hippo pathway.

scholarly journals SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sung Jun Bae ◽  
Lisheng Ni ◽  
Adam Osinski ◽  
Diana R Tomchick ◽  
Chad A Brautigam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Activation Loop ◽  
Hippo Signaling ◽  
Ww Domains ◽  
Kinase Activation ◽  
Genetic Ablation ◽  
Kinase Cascade ◽  
The Hippo Pathway

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

scholarly journals The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anke Hermann ◽  
Guangming Wu ◽  
Pavel I. Nedvetsky ◽  
Viktoria C. Brücher ◽  
Charlotte Egbring ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Cell Fate ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Large Tumor ◽  
Organ Growth ◽  
The Hippo Pathway

AbstractThe WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina. In summary, our data elucidate a novel role for Wwc2 as a key regulator in early embryonic development and sprouting angiogenesis in mice.

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